“The study shows that many genes central to insulin and glucagon production are regulated by differences in DNA methylation,” says Charlotte Ling, PhD, professor of epigenetics at Lund University and lead author of the study. “It has made it possible, for the first time, to describe detailed, cell-specific epigenetic patterns.”

The number of people living with diabetes is rapidly increasing worldwide, with approximately 95% of cases attributed to type 2 diabetes. This condition develops gradually and is characterized by a reduced ability to use insulin effectively, leading to elevated blood sugar levels. Over time, high blood sugar can lead to a range of complications that significantly impact the patient’s quality of life. 

Lifestyle factors like diet and physical activity are major drivers of this condition; however, genetics can also contribute to the development of type 2 diabetes, increasing the risk for some people over others. While genome- and epigenome-wide studies on diabetes have identified genetic and epigenetic mechanisms involved in type 2 diabetes, previous epigenetics studies had only looked at whole tissues and none had investigated epigenetic changes within specific cell types that are involved in blood sugar regulation. 

Ling’s team focused on alpha and beta pancreatic cells, which secrete insulin and glucagon hormones, respectively, to regulate blood sugar levels. By analyzing hundreds of thousands of cells from 24 people, with and without diabetes, the researchers created the most detailed epigenetics mapping of pancreatic cells to date. This allowed them to discover over 22,000 regions in nearly 8,000 genes that were differentially methylated between alpha and beta cells. 

“Here, for the first time, we show exactly which regions regulate insulin and glucagon production through DNA methylation, which gives us the opportunity to develop future treatments based on epigenetics,” says Ling.    

They then used CRISPR epigenetic editing to alter DNA methylation around the genes encoding for insulin and glucagon, which revealed that levels of the ONECUT2 transcription factor were elevated in beta cells from type 2 diabetes patients. This epigenetic upregulation was found to impair the ability of beta cells to release insulin, which in turn disrupted glucose regulation and reduced energy production within the cell.

Based on their findings, the researchers developed a web tool intended as a comprehensive resource available to researchers investigating the impact of age, sex, and type 2 diabetes on DNA methylation and gene expression in alpha and beta cells. 

“We now want to understand which of these changes can actually be reversed, and whether this can help beta cells regain their function in diabetes,” says Ling. “A key aspect is to see whether the effects of editing DNA methylation can be sustained in the cell over time.” 

The post Epigenetic Mapping in Pancreatic Cells Identifies New Diabetes Target appeared first on Inside Precision Medicine.

“The possibility of translating these findings into humans is very exciting,” said senior author Seung K. Kim, MD, PhD, a professor of developmental biology at Stanford. “The key steps in our study—which result in animals with a hybrid immune system containing cells from both the donor and the recipient—are already being used in the clinic for other conditions. We believe this approach will be transformative for people with type 1 diabetes or other autoimmune diseases, as well as for those who need solid organ transplants.”

Type 1 diabetes is an autoimmune disease that attacks pancreatic islet cells. While islet transplantation can restore insulin production, it typically requires immunosuppressive drugs that carry risks including infection, malignancy, and organ damage. The Stanford team’s approach reduced these negative effects by inducing immune tolerance through mixed hematopoietic chimerism, a state in which donor and recipient immune cells coexist.

“Mixed hematopoietic chimerism after hematopoietic cell transplantation (HCT) can modulate the immune system and induce tolerance to allogeneic tissues,” the researchers wrote. “However, bone marrow conditioning-related toxicities preclude wider adoption of HCT for transplant allotolerance.”

The current findings by the Stanford team builds on a series of research initiatives beginning with work published in 2022, in which the researchers showed they could cure toxin-induced diabetes in mouse models using antibody-based immune conditioning combined with moderate radiation (200–300 cGy), followed by transplantation of donor-matched blood stem cells and islets. This study served as a proof of concept but used radiation at levels that are potentially toxic.

A November study published in JCI, along with the new research addressed two significant challenges for developing an effective transplantation protocol: autoimmune diabetes, in which the immune system targets islet cells, and the need to reduce conditioning toxicity. In the November study, the researchers added an immune-modulating drug used in autoimmune disease to their regimen. This change enabled the formation of a hybrid immune system that both accepted donor islets and prevented autoimmune attack. All treated mice were protected from developing diabetes, and those with already possessing the disease were cured.

To further reduce toxicity, the April study added additional agents, baricitinib, venetoclax, and an αCD47 antibody, to go with αCD117 antibody and transient T cell depletion. These agents were selected because they target distinct biological pathways involved in immune regulation and bone marrow niche clearance. Baricitinib, a JAK1/2 inhibitor, reduces inflammatory signaling and supports donor cell engraftment. Venetoclax promotes apoptosis of specific immune cells, and αCD47 disrupts a signaling pathway that normally protects cells from clearance, which helped in the removal of host stem cells to make space for donor cells.

“We systematically tested baricitinib (JAK1/2 inhibitor), venetoclax (Bcl2 inhibitor), and αCD47 antibody, agents in current clinical use, and quantified hematopoietic chimerism after HCT,” the researchers wrote. “Combined with αCD117 antibody, transient T cell depletion, and just 10 centigray (cGy) total body irradiation (TBI), these agents enabled durable mixed chimerism and matching allo-islet tolerance, to cure diabetes without evidence of [graft-versus-host disease].”

This new combination allowed researchers to reduce radiation exposure to 10 cGy, a fraction of the levels used in conventional bone marrow transplantation. Mice treated using this regimen showed stable engraftment of donor cells, maintained fertility, and experienced no graft-versus-host disease. They also remained insulin-independent for the duration of the study.

The findings provide a potential pathway toward clinical adoption, which could be speedier than usual since many of the agents used for this approach are already approved or under evaluation in humans.

Work at Stanford will continue in this area and will focus on testing the reduced-intensity regimen in autoimmune diabetes models, refining conditioning strategies, and exploring alternative sources of islet cells, including those derived from stem cells.

If successfully, translated to the clinic, this treatment regimen could reduce or eliminate the need for lifelong insulin therapy, while expanding the use of transplantation-based therapies across a wider set of patients.

The post New Low-Toxicity Transplant Method Reverses Type 1 Diabetes in Mice appeared first on Inside Precision Medicine.

Researchers at the University of Lausanne have identified a specialized fibroblast population that actively organizes immune cell interactions within lymph nodes, revealing a key mechanism underlying effective T cell responses to infection and cancer.

The study, published in Immunity, shows that stromal cells, long considered primarily structural, play a central role in orchestrating where and how immune cells meet, with direct consequences for immune activation and memory formation.

Spatial organization drives immune efficiency

Lymph nodes act as surveillance hubs of the immune system, filtering lymphatic fluid and coordinating responses to pathogens or tumor cells. Within these small, highly organized structures, immune cells are not randomly distributed. Instead, they occupy defined niches that facilitate efficient communication.

Cytotoxic T lymphocytes (CTLs), for example, are typically positioned in central regions of the lymph node, where they interact with type 1 dendritic cells (cDC1s) that present antigen and initiate activation. As explained by the study authors, “cytotoxic T lymphocytes are typically found in central regions of the lymph node, where they colocalize and interact with specialized cells called type 1 dendritic cells that present danger signals to them.”

While the importance of this organization has long been appreciated, the mechanisms guiding immune cells to the correct locations have remained incompletely understood.

A fibroblast niche organizes T cell positioning

To address this question, the Lausanne team focused on fibroblasts, a class of stromal cells that form the structural backbone of lymphoid tissues. Using mouse models and human lymph node samples, they identified a distinct subset of fibroblasts located in the central compartment.

These fibroblasts are characterized by expression of MAdCAM1 and by their production of high levels of the chemokine CCL19. This signaling molecule acts as an attractant that guides cytotoxic T cells into proximity with dendritic cells, enabling productive immune interactions. As the researchers note, CCL19 “acts as an ‘attractant signal’ for cytotoxic T lymphocytes, bringing them into physical contact with type 1 dendritic cells.”

By shaping this spatial organization, the fibroblast subset creates a functional niche that promotes T cell activation. When this system was disrupted, cytotoxic T cells failed to position correctly and showed impaired differentiation into memory T cells, highlighting the importance of tissue architecture for long-term immunity.

Notch signaling maintains the stromal network

The researchers also identified the molecular pathway that sustains this fibroblast population. A signaling axis involving Notch2 and its downstream mediator RBPj was found to be essential for maintaining the identity and activity of the CCL19-producing fibroblasts.

In addition, Jagged-1, a ligand produced primarily by dendritic cells, appears to initiate or reinforce this signaling loop. This suggests a feedback mechanism in which immune cells and stromal cells cooperate to maintain the lymph node architecture.

According to the scientists, this pathway must remain active throughout life. When Notch2 signaling was disrupted in fibroblasts, the structural integrity of the niche was lost, leading to defective T cell responses and reduced formation of memory cells.

A conserved mechanism across immune tissues

Although the study focused on lymph nodes, the same organizational principles appear to extend to other immune organs. The researchers observed similar regulation of CCL19 production in the spleen and Peyer’s patches, which are involved in blood filtration and intestinal immunity.

Comparable fibroblast populations were also identified in human lymph nodes, suggesting that this mechanism is conserved across species and relevant to human immune function.

Implications for immunotherapy and vaccines

The findings add to a growing body of evidence that stromal cells play active roles in shaping immune responses. Rather than acting as passive scaffolds, fibroblasts help define where immune interactions occur and how effectively they proceed.

This has important implications for disease. In cancer, for example, ineffective T cell responses may result not only from intrinsic immune dysfunction but also from disrupted tissue organization that prevents optimal cell–cell interactions.

In vaccination, enhancing the formation or function of such stromal niches could improve immune activation and the development of long-lasting memory responses.

Looking ahead

The identification of a fibroblast-driven mechanism for organizing immune cell positioning provides a new foundation for understanding how immune responses are initiated and maintained.

Future research will be needed to explore whether targeting stromal signaling pathways, such as Notch2, can be used to modulate immune responses in therapeutic settings. While such approaches remain speculative, they highlight the potential of integrating tissue architecture into the design of next-generation immunotherapies.

“Overall, these findings deepen our understanding of the organization of the immune system and how effective T cell responses against infections and cancer are initiated,” said Sanjiv Luther, PhD, senior author of the study. “In the future, this knowledge could help improve vaccine design and clarify why immune defenses sometimes fail against certain pathogens or tumors.”

The post Fibroblast Subset Directs Immune Cell Positioning in Lymph Nodes appeared first on Inside Precision Medicine.

“Genetic mechanisms that predispose people to type 2 diabetes and cardiovascular disease remain poorly understood, partly because of a lack of sufficient data on non-European ethnic groups,” write the authors of the study, who were led by Dharambir K. Sanghera, PhD, director of the Genetic Epidemiology Laboratory at the University of Oklahoma Health Sciences Center. “Extending these evaluations to diverse cohorts is essential for gaining insights into the molecular pathways involved in disease.”

Sanghera and colleagues conducted a metabolite genome-wide association study to look for links between the human lipidome and cardiometabolic disorders in a Punjabi population originating from Northern India. Epidemiological studies have repeatedly shown that South Asians living abroad experience a higher incidence of type 2 diabetes and are more susceptible to cardiovascular disease compared to other ethnic groups. However, the exact mechanism responsible for this increased risk remains unknown and lipidomic and genome-wide data is lacking for Indian populations. 

“Genome-wide studies have shown that genes influencing blood lipid metabolites are often linked to different diseases,” write the study authors. “However, most of this research has been done on people of European ancestry. Studying more diverse populations is important to better understand how these genetic pathways contribute to disease in different ethnic groups.”

The study looked at genetic influences on 516 lipids in 3,000 Punjabi Sikh individuals and then validated the results in larger cohorts, with both European and non-European ancestry, using data from UK Biobank, GeneRISK, DIAMANT, PROMIS, and other studies. After multiple rounds of testing and correction, results showed strong associations in 36 pairs of lipid metabolites and single nucleotide polymorphisms (SNPs). Among them, 33 had not been reported before, and three were confirmed to be ancestry-specific. 

Further investigation identified a causal association between type 2 diabetes and the metabolite LPC O-16:0, which was paired with a genetic variant in the gene encoding for CD45, a key regulator of immune signaling. Another possible causal relationship was found with PC 38:4, a metabolite shown to protect against coronary artery disease in Indian populations that was paired with a genetic variant in an untranslated region of the FADS1/2 genes. 

“Our study has discovered new metabolite markers and genes that intersect with pathways of inflammation and immuno-vascular diseases, which have not been reported in previous European studies, specifically emphasizing how immune system signaling affects metabolic health,” state the authors. “By identifying unique genetic signatures in Asian Indians, the research advocates for ancestry-specific medical approaches to address chronic immuno-vascular conditions in cardiometabolic disease. These advances could be beneficial in clinical practice, enabling effective personalized therapies and preventive strategies.”

The post New Markers of Diabetes and Heart Disease Revealed via Genetic Study in Indians appeared first on Inside Precision Medicine.

The new findings build on data from the Vitamin D and Type 2 Diabetes (D2d) clinical trial, a multi-site randomized study that enrolled more than 2,000 U.S. adults with prediabetes. Study participants were assigned to receive either 4,000 IU of vitamin D3 daily or a placebo. The subjects were then followed for a median of 2.5 years to assess progression to diabetes. The original trial did not show a statistically significant reduction in diabetes risk across all participants.

“But the D2d results raised an important question: Could vitamin D still benefit some people?” said lead author Bess Dawson-Hughes, MD, a senior scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “Diabetes has so many serious complications that develop slowly over years. If we can delay the time period that an individual will spend living with diabetes, we can stop some of those harmful side effects or lessen their severity.”

In their follow-on research, the Tufts noted that subsequent analysis of the D2d trial data showed that outcomes varied based on achieved blood levels of vitamin D in participants. The new study also found a genetic link to those who had improved outcomes.

To explore the role genetics might play, the investigators conducted a post hoc analysis of 2,098 D2d participants who consented to genetic testing. They focused on three common polymorphisms in the vitamin D receptor (VDR) gene: ApaI, BsmI, and FokI. The researchers first examined how vitamin D levels correlated with diabetes risk across genotypes, then evaluated how genetic variants influenced response to supplementation.

The data showed that the ApaI polymorphism is a key determinant of response. Participants with the AA genotype, which was about 30% of the cohort, did not experience a reduction in diabetes risk with vitamin D supplementation. By comparison, those with the AC or CC genotypes, the remaining 70% of participants, showed a 19% lower risk of developing diabetes when treated with vitamin D compared with placebo.

The biological basis for this effect is linked to the role the VDR gene plays in pancreatic β cells, where it influences insulin secretion and glucose regulation. Variations in the receptor may alter how effectively vitamin D exerts these effects, explaining why some individuals benefit from supplementation while others do not.

Earlier research has suggested there is a connection between vitamin D and diabetes risk. In earlier analyses of the D2d trial, participants who maintained higher blood levels of vitamin D experienced substantial reductions in diabetes incidence. These findings were supported by meta-analyses and observational studies, including research from the UK Biobank, which found that genetic variation in VDR could modify its activity.

“We hypothesized that VDR gene variants modify the association between achieved intratrial 25-hydroxyvitamin D (25(OH)D) level and diabetes risk and may modify the effect of vitamin D3 supplementation on the risk of developing diabetes,” the researchers wrote. 25(OH)D is the main form of vitamin D circulating in the blood.

The current study broadens knowledge on the role vitamin D can play in diabetes prevention by identifying the specific polymorphisms at play. The overlap between ApaI and BsmI variants provides further evidence of the role of VDR genetics, although the researchers noted that ApaI alone may be sufficient to identify likely responders.

“This genetic association analysis of the D2d study suggests that genetic variation in the VDR, specifically the ApaI polymorphism, is associated with diabetes risk at higher intratrial 25(OH)D levels and is associated with response to 4000 IU/d of vitamin D3 supplementation among adults with prediabetes,” the researchers wrote.

The implications for clinical care include the potential use of genetic testing to guide preventive treatment. A single test for the ApaI polymorphism could help identify patients with prediabetes who are most likely to benefit from higher-dose vitamin D supplementation.

While the results have established a link between variations in the VDR gene and diabetes development, the research noted that the study was not designed to assess the mechanisms underlying the genetic effects. Further, its sample size limited subgroup analyses by race and ethnicity.

“Our findings suggest we may eventually be able to identify which patients with prediabetes are most likely to benefit from additional vitamin D supplementation,” Dawson-Hughes said. “In principle, this could involve a single, relatively inexpensive genetic test.”

Next steps in this line of research include replicating the findings in independent cohorts and conducting prospective trials designed to test genotype-guided supplementation strategies.

The post Vitamin D Linked to Lower Diabetes Risk in People with <i>VDR</i> Gene Variant appeared first on Inside Precision Medicine.

The SyntheMol-RL generative model, described in Molecular Systems Biology, could speed drug discovery and help in the fight against antibiotic resistance.

The algorithm uses reinforcement learning to rapidly design easily synthesizable small-molecule drug candidates from a massive chemical space of 46 billion compounds.

It created a compound that the researchers named synthecin, which was effective against MRSA wound infection in a mouse model, showing its utility for real-world drug discovery.

“We used our model to design new antibiotics, but it’s capable of so much more,” said researcher Jon Stokes, PhD, from McMaster University.

“We built it to be disease agnostic, meaning it could just as easily generate novel drug candidates for diabetes or cancer or other indications.”

The rapid spread of antibiotic resistance is a critical challenge facing modern medicine. In 2019, just under five million deaths were linked with drug-resistant bacteria and this number is expected to more than double by 2050 if the emergence of antimicrobial resistance continues to outpace the creation of new antibiotics.

Stokes and team examined whether SyntheMol-RL could identify potential antibiotics for MRSA, an infection listed by the World Health Organization as a high priority for new antibiotics.

It replaces SyntheMol, a previous incarnation that was not as effective for exploring the chemical space and was not able to optimize more than one molecular property, which is a necessity in real-world drug discovery.

The second-generation model uses reinforcement learning, which enables it to rapidly explore massive combinatorial chemical spaces with tens of billions of molecules for promising compounds that are easy to synthesize.

The researchers deployed SyntheMol-RL to identify compounds that simultaneously possessed the multiple drug-like properties of antibacterial activity against MRSA and aqueous solubility.

Next, they synthesized and experimentally tested 79 compounds designed by two variants of SyntheMol-RL and found a corresponding two and 11 potent hits.

One of these compounds, which they named synthecin, was able to fully arrest the growth of MRSA in a murine wound infection model.

“These results demonstrate that SyntheMol-RL is an effective and flexible framework for drug design applications,” the authors maintained.

They added: “SyntheMol-RL is compatible with any property predictor and combinatorial chemical space, it can be readily extended to a wide variety of drug discovery and molecular design problems.”

The post AI Tool Creates Designer Antibiotics appeared first on Inside Precision Medicine.

The intersection of geography and oncology is no longer a speculative frontier—it is rapidly becoming the new standard in understanding who gets cancer, who survives it, and why. At a recent session at AACR 2026 bringing together leading researchers from the Fred Hutch Cancer Center, Harvard, and UCSF, the consensus was clear: geospatial methods are fundamentally altering how epidemiologists interrogate the cancer continuum, from incidence to mortality, from prevention to palliative care.

Trang VoPham, PhD, from Fred Hutch opened proceedings with a sweeping overview of how location data is being weaponized against cancer disparities. Her team’s work exemplifies the field’s evolution beyond crude ecological fallacies toward granular, individual-level exposure assessment. “We linked geospatial data on agricultural pesticide operations with all death certificates in the U.S. from 1989 to 2023,” she explained, detailing their findings that higher linuron use correlated with a 16% increased risk of colorectal cancer mortality among under-50s—higher than the 11% seen in older populations. The precision matters: “It is absolutely critical… can you access or generate residential address histories, not just baseline, not just at diagnosis, to consider life course exposures, timing of exposures, during relevant and critical time periods?”

VoPham’s lab is already translating these insights into population health interventions. Their geoexmap web application—developed with community advisory boards across Washington State—enables neighborhood-level mapping of over 175 health variables, each paired with actionable mitigation strategies. “When you map radon, you can click on the tips button and see strategies for exposure mitigation, like where to get free radon test kits,” she noted. During 2023’s wildfire season, her team used Epic electronic health records to identify and contact 64,000 high-risk patients, resulting in over 4,000 same-day virtual primary care appointments. “This approach could absolutely be scaled to target other populations… to empower high-risk patients with information to help protect themselves from environmental hazards.”

Jaime Hart, ScD, from Harvard, shifted focus to the atmospheric dimensions of cancer risk, tracing how air pollution research has matured since IARC’s 2013 carcinogen declaration. She noted that evidence at the time was largely restricted to lung cancer data. Today, the picture has broadened considerably. Hart highlighted recent consortium work linking traffic-related nitrogen dioxide with premenopausal and Black women’s breast cancer risk—”mostly being driven by premenopausal breast cancer and breast cancer among Black women and non-Hispanic white women”—while PM2.5 associations remain more equivocal for this site.

The mechanistic sophistication has advanced in parallel. Hart detailed how particulate matter can “translocate across your lungs, get into your circulation and deposit in every tissue in your body,” even ascending the nasal pathway to breach the blood-brain barrier. Her collaboration with VoPham on wildfire-specific PM2.5 revealed that “even for the same increase in air pollution exposure… if that PM2.5 is coming more from wildfires than not, you saw an elevated risk,” suggesting source-specific toxicity profiles that carry profound regulatory implications.

Iona Cheng, PhD, from University of California, San Francisco, anchored the session in the structural determinants that underlie these spatial patterns. Her work on redlining—historical mortgage discrimination encoded into contemporary health disparities—demonstrates how geospatial tools can excavate systemic injustice. “In Detroit… about 70% [of non-Hispanic white men with prostate cancer] do live in an area that has not been redlined, in contrast to about 30%,” she reported, whereas “almost 60%” of African American patients resided in the most heavily denied neighborhoods. The mortality gradient was stark: “Higher prostate cancer mortality, or lower survival, associated with living in neighborhoods with more redlining, for both Black and white men.”

Cheng emphasized that these are not proxy measures for individual behavior but independent contextual effects. “We do see that the neighborhood itself has contributions,” she said, describing how her team is developing racially-ethnic-specific composite indices of structural racism across housing, education, employment, and judicial domains. The community-engaged methodology proved essential: working with Hawaiian advisory boards revealed that non-Hispanic white reference groups made little demographic sense for the islands, prompting recalibration.

The session closed with a palpable sense of acceleration. From Google’s nascent geospatial reasoning AI to wearable sensor validation of satellite models; from street-view imagery classifying 350 million U.S. locations to ecological momentary assessment tracking real-time exposures, the toolkit is expanding exponentially. As Hart observed: “The places where we live, work, and play influence our risk of cancer, impose diagnostic outcomes. There are robust biological mechanisms that underlie this.” The geospatial revolution in cancer epidemiology, it seems, is only getting started.

The post How Geospatial Science is Reshaping Cancer Epidemiology: Three Perspectives from the Front Lines appeared first on Inside Precision Medicine.

The genetic association study indicated that individuals with glycemic indicators of prediabetes could benefit from supplementation with 4000 IU/d of vitamin D₃ if they carried specific genetic polymorphisms.

Two genotypes of the ApaI vitamin D receptor polymorphism (VDR) were linked to a risk reduction when these vitamin supplements were taken compared with placebo, according to the report in JAMA Open.

“Our exploratory findings, if confirmed, hold promise for high-dose vitamin D₃ as a targeted, personalized approach to reducing the risk of type 2 diabetes among selected adults with prediabetes,” reported Bess Dawson-Hughes, MD, from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, and co-workers.

“The magnitude of the observed risk reduction among participants with AC and CC alleles of the ApaI polymorphism, if confirmed in an independent clinical trial, would have clinical implications for the management of prediabetes.”

There are four major polymorphisms in the vitamin D receptor: FokI, BsmI, ApaI, and TaqI. While the FokI polymorphism produces a shorter vitamin D receptor with enhanced transcriptional activity, the BsmI, ApaI, and TaqI polymorphisms influence mRNA stability, posttranscriptional regulation, and translational efficiency.

ApaI is strongly associated with metabolic syndrome and obesity, which are both major risk factors for type 2 diabetes.

In an extended analysis of the Vitamin D and Type 2 Diabetes (D2d) trial, researchers examined whether VDR gene variants modified the results of the trial.

The primary outcome of the original trial, conducted in people who achieved at least two of the three glycemic criteria for prediabetes, did not reach statistical significance in the intention-to-treat analysis. However, further examination revealed that the effect of vitamin D₃ depended on the achieved intratrial serum 25-hydroxyvitamin D (25[OH]D) levels.

Dawson-Hughes and team therefore examined common VDR polymorphisms in the D2d trial to see whether these polymorphisms were associated with reduced diabetes risk among participants who achieved higher intratrial mean 25(OH)D level, in a discovery-level analysis.

They then conducted a test phase to determine whether participants’ VDR genetic profile modified the response to vitamin D₃ supplementation compared with placebo.

Among 2098 participants in the D2d trial, the 618 carrying the AA alleles experienced no reduction in risk of progression to type 2 diabetes either when achieving higher intratrial 25(OH)D concentrations or when using vitamin D₃ 4000 IUs per day for a median of 2.5 years after adjusting for race, sex, and body mass index, among other variables.

However, the 1480 participants with ApaI AC and CC genotypes—representing 71% of the study population—had a progressively lower risk of type 2 diabetes at intratrial 25(OH)D levels of 40 ng/ml or higher.

Participants with these genotypes had a 19% reduction in the risk of progressing to type 2 diabetes over the same period (Hazard ratio=0.81).

“If confirmed, a 19% risk reduction in conversion to type 2 diabetes with vitamin D₃ supplementation would not be trivial,” the authors concluded, noting that assessment of a single VDR polymorphism is inexpensive and now widely available.

In a Commentary article accompanying the study, Michael Holick, PhD, and Arash Shirvani, PhD, both from Boston University, added: “The enormity of the disease burden of diabetes worldwide and the confirmation that vitamin D supplementation of 4000 IUs per day markedly reduces risk of developing it should be a wake-up call and the impetus for health organizations to develop strategies to improve vitamin D status for children and adults with food fortification programs, implementation of supplementation, and sensible sun exposure recommendations for those who are at risk.”

The post Prediabetes Genotyping Identifies Who Benefits from Vitamin D appeared first on Inside Precision Medicine.

“We also found that this transformation of the local neighborhood is reversible, if caught early enough. This opens the door to new treatment and prevention strategies,” said senior author Joo-Hyeon Lee, PhD, an associate member in the developmental biology program at MSK.

The research focused on lung alveolar type II (AT2) stem cells that acquire mutations in the KRAS gene. Rather than simply proliferating, the mutant cells enter a regenerative-like state that resembles tissue repair. In this state, they produce amphiregulin (AREG), a signaling molecule that initiates communication with surrounding cells. AREG activates nearby fibroblasts through EGFR signaling, which prompts them to adopt a fibrotic, injury-like state which results in a remodeling of the extracellular matrix.

Within the microenvironment created, fibroblasts play a central role in shielding emerging tumor cells by producing a fibrous scaffold that supports tumor growth while also releasing signals that alter the activity of immune cells. Macrophages recruited to the site undergo reprogramming, shifting away from fighting the tumor toward phenotypes that suppress immune responses. Neutrophils and regulatory T cells are also recruited, further dampening anti-tumor immunity. This coordinated activity creates a protective niche in which the cells with the KRAS mutation can grow without being eliminated.

“These reciprocal interactions establish a self-sustaining epithelial–stromal–immune circuit that generates a tumor-permissive niche before malignant outgrowth,” the researches wrote. This loop reinforces itself: mutant cells sustain fibroblast activation, fibroblasts reshape immune responses, and immune cells further support tumor-promoting conditions.

The study builds on prior research in the Lee lab into lung injury and repair, which showed that normal regenerative programs involve temporary activation of stem cells and fibroblasts. In cancer, however, this process becomes dysregulated. Mutant cells remain locked in a regenerative state, continuously signaling to their environment. Earlier work by the same group had identified these regenerative states as a feature of early tumorigenesis.

To identify the mechanisms involved, the MSK first used mouse models of lung cancer carrying KRAS mutations. Through lineage tracing and single-cell analyses, they tracked individual cells to map how interactions with fibroblasts and immune cells evolved over time. They then used tissue samples from patients with early-stage lung adenocarcinoma and found returned the same result of cancer cells producing high levels of AREG and adjacent fibrotic fibroblasts.

Importantly, the team demonstrated that disrupting this communication network can prevent tumor formation. Blocking AREG signaling with an EGFR inhibitor kept fibroblasts and immune cells in their normal states and significantly impaired tumor development. Similarly, removing the AREG gene from mutant cells prevented the formation of the tumor-supportive niche. Even after early lesions had formed, inhibiting KRAS activity reversed many of the changes that had already occurred in the microenvironment.

The implications of this research to influence for cancer care are substantial. The identification of early signaling events and microenvironmental changes suggests new biomarkers for detecting lung cancer before it becomes advanced. High levels of AREG or evidence of fibroblast activation could indicate the presence of precancerous lesions, which could be particularly important for screening those at high risk of developing cancer, such as long-term smokers.

The findings also suggest there could be the development of new therapeutics aimed at preventing cancer development as opposed to treating it once it is established. By targeting the AREG–EGFR signaling axis or disrupting fibroblast activation, clinicians may be able to block tumor development at its earliest stages. Because the team showed these processes can be reversed, there is a window for intervention before the disease becomes resistant to treatment.

“The reversibility of these preneoplastic circuits defines a therapeutic window before progression to treatment-resistant disease,” the researchers wrote.

Next steps for the team include validating biomarkers in clinical populations, refining organoid models to study patient-specific tumor development, and testing preventive therapies that target these newly identified early signaling pathways.

The post Earliest Events of Lung Cancer Development Mapped appeared first on Inside Precision Medicine.

A new study published in Nature Communications is reshaping how researchers think about metastasis, showing that the cells most likely to spread are not defined by extremes, but by a precise balance of biological states within the primary tumor.

The work, led by Raúl Jiménez Castaño, PhD, and colleagues in the Cell Plasticity in Development and Disease Laboratory headed by Ángela Nieto at the Instituto de Neurociencias in Spain, identifies a nonlinear relationship between expression of the transcription factor Prrx1 and metastatic potential in breast cancer. Tumors with intermediate levels of Prrx1—not low or high—were found to be the most metastatic.

“This is unusual,” Jiménez Castaño said. “You normally expect a linear correlation—either low or high expression being the most relevant. But here, the peak of metastasis is in the intermediate levels.”

From paradox to mechanism

The study builds on longstanding efforts to understand the epithelial-to-mesenchymal transition (EMT), a developmental program that enables cells to migrate and is co-opted by cancer cells during metastasis. While EMT has been widely linked to tumor dissemination, the new findings show that metastatic potential is not simply a function of how invasive a cell becomes. Instead, it depends on a finely tuned balance between invasion and proliferation—two processes that are often at odds.

Previous work from the group and others had produced conflicting results regarding the role of Prrx1. In some models, removing the gene reduced metastasis; in others, it appeared necessary for dissemination. To resolve this contradiction, the researchers turned to patient tumor samples, where they observed that metastatic incidence peaked in tumors with intermediate Prrx1 expression.

Modeling a metastatic “sweet spot”

To investigate, the team engineered mouse models with graded levels of Prrx1 expression, mimicking the spectrum observed in human tumors. The results closely mirrored patient data. Tumors lacking Prrx1 showed little ability to metastasize, while those with high expression were capable of invasion but produced relatively few metastases. In contrast, tumors with intermediate levels generated the highest metastatic burden.

At the invasive front of these tumors, the researchers identified a distinct population of cells capable of both migrating and adopting divergent fates—either proliferating or entering a dormant state. This balance proved to be the critical determinant of metastatic success.

To understand the underlying biology, the team applied a range of advanced techniques, including single-cell RNA sequencing, chromatin profiling, and spatial transcriptomics. These approaches allowed them to map cellular states within tumors and link Prrx1 expression levels to functional behavior.

The analyses revealed that Prrx1 plays a dual role: it promotes invasion while simultaneously activating a dormancy program that suppresses cell division.

“At the same time that Prrx1 is necessary for cancer cells to be invasive, it also activates a dormancy program,” Jiménez Castaño explained.

This creates a biological trade-off. At high Prrx1 levels, cells are highly invasive but largely non-proliferative, limiting their ability to form metastases. At low levels, cells retain proliferative capacity but cannot effectively disseminate. Only at intermediate levels do cells achieve both capabilities.

“If the cancer cell has these intermediate levels, it is both invasive and proliferative,” he said. “And therefore, these cells will create a lot of metastasis.”

Metastatic potential begins in the primary tumor

One of the study’s most significant implications is that metastatic potential is determined earlier than previously appreciated. Rather than being dictated solely by conditions at distant sites, the ability of cancer cells to form metastases appears to be encoded within specific cell states in the primary tumor.

“The big conclusion is that already in the primary tumor, the potential of the cancer cells to metastasize is defined,” Jiménez Castaño said.

This finding aligns with broader observations from the field that tumors contain heterogeneous populations of cells with distinct functional properties. In this case, a subset of cells with intermediate Prrx1 expression represents a particularly dangerous state—one that combines mobility with the capacity for sustained growth.

Implications for biomarkers and therapy

Although the study identifies Prrx1 as a potential marker of metastatic risk, translating this insight into clinical practice will require further validation. The researchers were able to stratify tumors into low, intermediate, and high expression groups using staining intensity and computational analysis, but defining precise thresholds remains a challenge.

“We cannot say at this moment it is a biomarker,” Jiménez Castaño noted.

Even so, the findings provide a conceptual framework for improving patient stratification and identifying tumors with a higher likelihood of metastasis.

They also suggest new therapeutic strategies. Rather than attempting to eliminate invasive behavior entirely, it may be possible to push tumor cells into states that are less capable of forming metastases. For example, maintaining high Prrx1 expression could promote invasion while simultaneously enforcing dormancy, preventing metastatic outgrowth.

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