Biology subjects

Gulay, K.

Publications and source records attributed to Gulay, K..

3 recordsLinked to original sources

bioRxiv2025

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy. However, resistance remains a major hurdle in clinical care. Resistance can arise from microenvironmental metabolites or through direct metabolic reprogramming of pancreatic cancer cells. Here, we generated PDAC models of acquired gemcitabine resistance to determine the relationship between these mechanisms. We observed that physiological levels of exogenous pyrimidines have a diminished ability to impact gemcitabine response in PDAC cells with acquired resistance. This occurs as the metabolic reprogramming of PDAC cells in response to gemcitabine treatment forces a suppression of the pyrimidine salvage pathway. Importantly, this metabolic rewiring renders gemcitabine-resistant PDAC cells highly susceptible to inhibition of the rate limiting enzyme of the mevalonate biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), using statins. Notably, statin treatment inhibits the growth of gemcitabine-resistant tumors in immunocompetent mouse models. Through metabolite rescue experiments, we identified geranylgeranyl pyrophosphate as the critical metabolite lost during statin treatment, resulting in reduced protein geranylation in PDAC cells. Finally, as downregulation of the HMGCR is gradually acquired during gemcitabine resistance, we observed that HMGCR expression predicts patient response to gemcitabine. Collectively, these data demonstrate that the mevalonate biosynthesis pathway represents a promising therapeutic target in gemcitabine resistance and may serve as a biomarker to stratify treatment selection in PDAC patients.

cancer biology↗

bioRxiv2025

Redirecting cytomegalovirus immunity against pancreas cancer for immunotherapy

Immunotherapy shows limited success in pancreatic cancer, largely due to a low mutational burden and immunosuppressive microenvironment. Here we hypothesized that pre-existing antiviral immunity can be redirected to control pancreatic tumors. Cytomegalovirus (CMV, a {beta}-herpesvirus) was chosen, as the majority of the population is infected and it induces an extremely large/broad memory T cell response. Mice latently infected with murine CMV (MCMV) were orthotopically implanted with pancreatic cancer cells and treated with systemic injections of MCMV T-cell epitopes. The therapy promoted preferential accumulation of MCMV-specific T cells within pancreatic tumors, delaying tumor growth and increasing survival. Immunophenotyping and scRNAseq analyses showed these T cells were highly activated and cytotoxic, leading to increased tumor necrosis and caspase-3 activation. Finally, therapy was enhanced when combined with subtherapeutic doses of gemcitabine chemotherapy. Together, these results show that CMV-specific T cells can be repurposed to combat pancreatic cancer. SignificanceOur studies reveal that CMV-specific viral memory T cells can be re-directed to control a solid tumor normally refractory to immunotherapy via a simple, intravenous injection of T cell peptide epitopes. This mutation agnostic approach has significant potential for the development of "off-the-shelf" therapeutics by stimulating pre-existing antiviral memory and it is widely applicable due to the high prevalence of CMV.

cancer biology↗

bioRxiv2024

MICAL2 Is a Super Enhancer Associated Gene that Promotes Pancreatic Cancer Growth and Metastasis

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed that MICAL2 is a super enhancer-associated gene in human PDAC. MICAL2 is a flavin monooxygenase that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin related transcription factors (MRTF-A and MRTF-B). We found that MICAL2 is overexpressed in PDAC and correlates with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, we observed that MICAL2 promotes both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 expression also inhibited macropinocytosis. Through in vitro phenotypic analyses, we show that MICAL2, MRTF-A and MRTF-B influence PDAC cell proliferation, migration and promote cell cycle progression. Importantly, we demonstrate that MICAL2 is essential for in vivo tumor growth and metastasis. Interestingly, we find that MRTF-B, but not MRTF-A, phenocopies MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 impacts PDAC biology and suggests that its inhibition may impede PDAC progression. Our results provide a foundation for future investigations into the role of MICAL2 in PDAC and its potential as a target for therapeutic intervention.

cancer biology↗