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Phenotype screens of murine pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like neural invasion

ABSTRACT: Phenotype screens of murine pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like neural invasion

PROVIDER: PRJNA1026982 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26359300_1.fastq.gz	Fastqsanger.gz
	SRR26359300_2.fastq.gz	Fastqsanger.gz
	SRR26359301_1.fastq.gz	Fastqsanger.gz
	SRR26359301_2.fastq.gz	Fastqsanger.gz
	SRR26359302_1.fastq.gz	Fastqsanger.gz

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Phenotype screens of murine pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like neural invasion

Project description:Solid cancers like pancreatic cancer (PDAC) frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modelled in genetically-engineered mouse models (GEMM) of PDAC.Here, we systematically screened for human-like NI in Europe’s largest repository of GEMM of PDAC comprising 295 different genotypes. This phenotype screen uncovered two GEMM of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming-growth-factor-alpha (TGFa) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGFa upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI, and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGFa-expression constituted strong prognostic factors. Therefore, TGFa-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

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