Chhoda, Ankit

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy due in part to metabolic rewiring and a high rate of metastasis. Pancreatic tumors are particularly dependent upon glutamine (Gln) as a nutrient source for multiple metabolic pathways. To adapt to low levels of glutamine, PDAC cells upregulate the Rac1 dependent process of macropinocytosis, which internalizes extracellular macromolecules to scavenge them as a glutamine source. The proto oncogene Vav1 is an activator of the potent Rac/Cdc42 signaling cascades that regulate actin dynamics. While Vav1 is normally restricted to hematopoietic cells, Vav1 expression is significantly increased in PDAC, with high Vav1 correlating with worse overall survival. Here we uncover a novel Vav1 mediated regulation of glutamine metabolism in PDAC cells. While Vav1 is a potent activator of Rac1, surprisingly, Vav1 expression inhibited macropinocytosis in PDAC cells. Intriguingly, genomic and metabolomic analysis revealed that high Vav1 expression correlates with increased dependence on glutamine and glutamate (Glu) metabolism. Indeed, Vav1 dependent macropinocytosis was rescued by cell permeable glutamate, confirming disrupted Gln/Glu balance in Vav1 knockdown cells. RPPA screening indicated a Vav1 dependent effect on glutaminase 1 (GLS1, KGA isoform), which converts glutamine to glutamate. Mechanistically, we discovered that Vav1 modulates GLS1 localization to the mitochondria through regulation of GLS1 posttranslational modification. Disrupting GLS1 localization by deleting its mitochondrial targeting motif phenocopied loss of Vav1 in reducing the invasive potential of tumor cells. Investigation of Vav1 dependent metabolic consequences showed that knockdown of Vav1 alters 13C Gln derived metabolic flux into the TCA cycle, as well as a deficiency in the level of the antioxidant glutathione (GSH), which utilizes glutamate for its synthesis. Consequently, targeting Vav1 resulted in increased levels of cellular and mitochondrial reactive oxygen species (ROS) and increased sensitivity to lipid peroxidation. Notably, dual targeting of both glucose and glutamine pathways showed significant synergistic effects on cellular viability in Vav1 expressing cells. Here we established a new tumor promoting role for Vav1 via Gln/Glu regulation and uncover a novel subcellular regulation of mitochondrial glutamine metabolism. Our findings establish Vav1 as a critical regulator of metabolic rewiring in PDAC and orchestrates glutamine metabolism by controlling the KGA isoform of GLS1 mitochondrial localization. Importantly, Vav1 functions as a signaling adapter in glutamine metabolism, providing a potential therapeutic vulnerabilities for PDAC patients with high Vav1 expression. Citation Format: Mustafa Emre Gedik, Omar L. Gutierrez-Ruiz, Katherine M. Johnson, Ella Rose D. Chianis, Jing Chen, Alex Bittner, Adam Zahm, Ankit Chhoda, Taro Hitosugi, Mark A. McNiven, Gina Razidlo. Vav1 promotes pancreatic tumor cell invasion via GLS1-dependent glutamine metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7322.

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.

AbstractSurveillance of individuals at high‐risk of pancreatic cancer using CAPS criteria and other expert consensus guidelines may result in earlier pancreatic cancer detection in some cases; therefore, clinicians are responsible for appropriately identifying and referring these individuals to appropriate high‐risk pancreas cancer screening programs. This study aimed at assessing the perspective, knowledge, and clinical practices of cancer genetic counselors surveyed nationwide towards identification of individuals at high‐risk of pancreatic cancer and utilization of high‐risk pancreatic cancer screening programs. One hundred and eighty‐nine genetic counselors who listed “Cancer” as their specialty on the NSGC website responded to the survey, which consisted of multiple practice‐based, knowledge‐based, and clinical vignette‐based questions. Almost 70% of the genetic counselors surveyed accurately identified when an individual would be considered for high‐risk pancreatic cancer screening, when using 2019 CAPS consensus guidelines as a benchmark. Access to high‐risk pancreatic cancer screening programs and increased provider comfort in counseling individuals at high‐risk of pancreatic cancer were found to be statistically associated in accurate identification of high‐risk individuals in three of the clinical vignettes. Additionally, 60% of genetic counselors reported the majority of high‐risk individuals accept a referral for pancreatic cancer screening, which shows a high uptake of patients accepting referrals from genetic counselors. Genetic counselors have high accuracy in determining who is eligible for high‐risk pancreas screening; thus, they are the ideal providers for initiating referrals to high‐risk pancreatic cancer screening programs. Genetic counseling programs and high‐risk pancreatic cancer screening programs should establish a close working relationship to optimize the identification and subsequent referrals of high‐risk individuals eligible for pancreas cancer screening.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is frequently used to risk-stratify pancreatic cystic lesions (PCLs). Rising PCL incidence and developments in tissue acquisition and specimen analysis necessitate updated appraisal of EUS-FNA safety, particularly the risk of postprocedure pancreatitis, the most common EUS-FNA-related adverse event. Our systematic review aims to accurately quantify the risk of EUS-FNA-related pancreatitis to best inform decisions regarding EUS-FNA's optimal role in PCL workup. METHODS: We performed systematic searches in 4 databases from inception to April 2024 for original English-language studies investigating EUS-FNA-related pancreatitis. We extracted data on demographics and EUS-FNA-related pancreatitis risk, severity, and risk factors. These were meta-analyzed through the DerSimonian Laird Method using a random-effects model. Meta-regression of pancreatitis risk was performed to delineate associations with clinical and procedural characteristics. RESULTS: Sixty-four studies comprised 8,086 patients and reported 110 EUS-FNA-related pancreatitis events. Pooled risk of EUS-FNA-related pancreatitis was 1.4% (95% confidence intervals, −0.8% to 3.5%; I 2 = 0.00), which was predominantly of mild severity (67%) and uniformly nonfatal. Pancreatitis risk lacked significant association with sample size, age, sex, cyst size, needle caliber, or passes, although we noted trends toward higher risk in studies published after 2015, those using higher gauge needles (19 G vs 22 G/25 G), and those performing EUS-guided through-the-needle biopsy. DISCUSSION: We note with high certainty that pancreatitis after EUS-FNA of PCLs is infrequent and mild in severity with no mortality in the included cohort. EUS-guided through-the-needle biopsy may serve as a significant risk factor for EUS-FNA-related pancreatitis risk; however, further studies are needed to delineate other predisposing characteristics.

AbstractBackgroundIdentifying branch‐duct intraductal papillary mucinous neoplasms (BD‐IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance.ObjectiveWe aimed to externally validate the previously developed Dutch‐American Risk stratification Tool (DART‐1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high‐risk stigmata (HRS).MethodsThree prospective cohorts of individuals under surveillance for BD‐IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART‐1, a multivariable Cox‐proportional logistic regression model with five predictors for the development of WFs or HRS.ResultsOf 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART‐1's discriminative ability (C‐statistic 0.68) was similar to that in the development cohort (0.64–0.72) and showed moderate calibration. DART‐1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3‐year risk was 0%–0% versus 0%–3.7% for Q1; 0.3%–0.4% versus 3%–11% for Q2; and 2.6%–3% versus 2.4%–9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%).ConclusionsThe performance of DART‐1 to predict the development of WFs or HRS in BD‐IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD‐IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.