Dataset Information

Genome wide gene expression profile of pancreatic ductal adenocarcinoma (PDAC) cells after knock down of focal adhesion kinase (FAK).

ABSTRACT: In our experiments, we showed that FAK regulates PDAC clonogenicity and selfrenewal. In order to evaluate the impact of FAK knockdown on the transcriptomes of PDAC , we knocked down FAK in two PDAC cell lines and compared the gene expression signatures with the cancer stem cell (CSC)associated gene signatures by GSEA analysis. CCS related gene profile was inversely related with FAK-knockdown gene signature.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97488 | GEO | 2017/04/20

SECONDARY ACCESSION(S): PRJNA381967

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

Dataset Information

Genome wide gene expression profile of pancreatic ductal adenocarcinoma (PDAC) cells after knock down of focal adhesion kinase (FAK).

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