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A cancer associated fibroblast hierarchy driven by mutant p53 induces perlecan deposition in the pancreatic tumor stroma to permit metastasis and impairs response to chemotherapy

ABSTRACT: Heterogeneous sub-populations of cancer cells exist within pancreatic tumors and shape the local stroma. Recent studies have provided evidence that subtypes of cancer-associated fibroblasts (CAFs) also coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 (loss or gain-of-function) manipulate CAFs using matched CAFs and cancer cells isolated from the low metastatic KPflC (p53 null) and highly metastatic KPC (gain-of-function p53 mutant) mouse models of pancreatic cancer. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that drive the establishment of a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. Using proteomic characterization of CAF secretomes combined with CRISPR-Cas9 based editing identified perlecan as a key component of this pro-metastatic and resistant environment. Lastly, using longitudinal intravital imaging with a CDK1 FRET reporter and titanium windows, we observe that these dominant CAFs delay cancer cell response to gemcitabine/Abraxane in both GOF and null p53 cancer cells. We also reveal that depletion of perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential novel target for development of anti-stromal therapies in pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE123646 | GEO | 2019/06/06

REPOSITORIES: GEO

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