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RNA-seq of a mouse primary pancreatic cancer cell line and liver metastasis from mouse model INK4.1syn_Luc

ABSTRACT: The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor. We detected an upregulation of the secreted axon guidance molecule Netrin-1 (Ntn1) in human and mouse PDAC metastases that signals through its receptor, uncoordinated- 5b (Unc5b) to facilitate metastasis in vitro and in vivo. The mechanism of Ntn1 induction in liver metastasis is mediated by hepatic stellate cell (HSC) secreted retinoic acid through RXR/RAR and Elf3 signaling. Ntn1 is present in PDAC-derived extracellular vesicles (EVs) and facilitates metastasis by inducing HSC activation through both long and short distance intercellular communication. Importantly, administration of a neutralizing monoclonal NTN1 antibody decreased metastases and increased survival in several murine PDAC models (autochthonous and metastatic). Our studies reveal a new metabolic feed-forward loop for metastatic niche formation in the liver involving NTN1 in PDAC-secreted EVs and retinoic acid released from HSCs which is targetable using anti-NTN1 therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE245306 | GEO | 2023/10/31

REPOSITORIES: GEO

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