Biology subjects

Cognet, G.

Publications and source records attributed to Cognet, G..

4 recordsLinked to original sources

bioRxiv2025

Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer

Systemic therapies are the standard of care for most pancreatic ductal adenocarcinoma (PDAC) patients but provide limited benefit due to pervasive resistance. The fibrotic tumor microenvironment (TME) is thought to drive resistance by restricting perfusion and drug delivery. Here, we show that therapeutically relevant drug concentrations are achieved even in poorly perfused, therapy-resistant murine PDAC tumors, indicating that impaired delivery alone does not explain drug resistance. Instead, we find TME exposure imprints a therapy-resistant state upon PDAC cells. These observations raised the question of how the TME imposes this state. Poor perfusion alters nutrient availability in the TME. To model this, we developed Tumor Interstitial Fluid Medium (TIFM), which recapitulates TME nutrient conditions. TIFM cultured PDAC cells acquire a therapy-resistant phenotype that mirrors resistance observed in the TME. In this state, cytotoxic and targeted therapies retain on-target activity but fail to trigger cell death, resulting in therapeutic tolerance. Mechanistically, drug tolerance is driven by suppression of apoptotic priming and can be reversed by inhibition of the anti-apoptotic regulator BCL-XL. These results identify TME-driven reprogramming of cell death as a key mechanism of therapy resistance in PDAC and establish TIFM as a physiologically relevant model for studying microenvironment-induced drug resistance.

cancer biology↗

bioRxiv2025

Microglial Fructose Metabolism Is Essential for Glioblastoma Growth

Glioblastoma (GBM) is most common and aggressive primary brain tumor in adults, for which standard of care hasnt changed in twenty years. GBM tumor associated macrophages (TAMCs), consisting of infiltrating myeloid cells from the periphery and resident microglia cells, are pro-tumorigenic, promoting tumor growth. Fructose is one of the most abundant metabolites in the GBM tumor microenvironment (TME), as well as in the healthy central nervous system (CNS). In the CNS and GBM, microglia are the predominant expressors of the fructose transporter GLUT5. Mice lacking the GLUT5 transporter (GLUT5-KO) survive significantly longer after orthotopic implantation of two glioma cell lines than wildtype mice, which is not due to dietary fructose or peripherally derived TAMCs. Investigation of the TME showed that GLUT5-KO mice have more highly activated and inflammatory innate and adaptive immune compartments. Microglia cultured in fructose have a decreased phagocytic ability and exhibit decreased inflammatory capacity due to the polyol pathway promoting redox homeostasis.

cancer biology↗

bioRxiv2025

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis

Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

cancer biology↗

bioRxiv2020

Mitochondrial determinants of response and resistance to venetoclax plus cytarabine duplet therapy in acute myeloid leukemia

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen.

cancer biology↗