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

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

PROVIDER: PRJNA1311024 | ENA |

REPOSITORIES: ENA

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

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

| PRJNA1427604 | ENA

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

Project description:Cytotoxic chemotherapy remains the standard-of-care treatment for patients with pancreatic ductal adenocarcinoma (PDAC). However, chemotherapy only has modest effects at improving overall survival due to primary or rapidly acquired chemoresistance. The biological underpinnings of PDAC therapy resistance are incompletely defined, but the tumor microenvironment is known to be a major contributor to chemoresistance. We have found chemoresistance is imprinted on PDAC cells by the tumor microenvironment and persists for a period of days after PDAC cells are removed from tumors. However, PDAC chemoresistance is lost upon long term culture in standard laboratory conditions. Interestingly, culture of PDAC cells in Tumor Interstitial Fluid Medium (TIFM), a culture medium we developed to recapitulate the nutrient availability of the tumor microenvironment, maintains PDAC cells in a chemoresistant state even after long term culture ex vivo. These findings suggest that microenvironmental metabolic stress keeps PDAC cells in a physiologically relevant, therapy resistant cell state that standard culture models fail to maintain. Using TIFM culture, we sought to understand how PDAC cells in this state resist chemotherapeutic challenge. We found that chemotherapy drugs largely retain on-target activity within TIFM medium but fail to activate cell death, enabling a “chemotolerant” cell state, which is also observed in PDAC tumors. This chemotolerant state is driven by suppression of apoptotic priming and can be overcome by targeting the anti-apoptotic regulator BCL-xL. Taken together, these findings suggest that reprogramming of cell death mechanisms by the PDAC nutrient microenvironment is a key contributor to therapy resistance in this disease.

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

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Ontogeny and Vulnerability of Lapatinib Drug-Tolerant Persisters in HER2-positive Breast Cancer

Project description:Despite advances in HER2-targeted therapeutics, resistance remains a significant clinical problem in HER2-positive (HER2+) breast cancer, especially in the metastatic setting. Drug-tolerant persisters (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs for HER2-targeted TKIs have not been characterized extensively. We found that upon treatment with the TKI lapatinib, HER2+ breast cancer lines yielded DTPs with luminal-like or mesenchymal-like transcriptional programs and differential sensitivity to lapatinib/anti-estradiol combinations. Lentiviral barcoding and single cell RNA-sequencing indicate that HER2+/ER+ cells cycle stochastically through a pre-DTP state, characterized by a G0-like signature, which uniquely gives rise to DTPs upon lapatinib exposure.

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An isogenic E. coli population gives rise to multiple persister phenotypes

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