Deciphering the molecular dialogue between cancer-associated fibroblasts and tumor cells in ATM-deficient pancreatic cancer

Pancreatic ductal adenocarcinoma (PDACs) are aggressive cancers characterized by a dense tumor stroma enriched in signaling factors and supporting tumor progression. Multiple studies highlight the dynamic tumor-stroma dialog, notably including cancer-associated fibroblasts (CAFs). Recently, various populations of CAFs (e.g., inflammatory iCAF and myofibroblastic myCAF) have been identified and associated with distinct functions, promoting or restraining tumor progression. It appears that iCAF and myCAF differentiation is governed by molecular signaling from epithelial tumor cells. We demonstrated that the loss of the DNA damage response gene ATM serine/threonine kinase is associated with a mesenchymal phenotype and a prominent desmoplastic reaction. In such a context, we suggest that ATM-deficient pancreatic cancer cells might crosstalk with fibroblasts and specifically redraft PDAC stroma microenvironment, which in turn could support tumor progression. To decipher how ATM status might affect PDAC tumor stroma reprogramming, and because there is increasing evidence that disease progression of ATM-deficient PDAC depends on the mutational status of Trp53, we used ATM and/or P53-depleted cell lines established from our KC (LSL-Kras^G12D/+; Ptf1a^Cre/+ ), AKC (Atm^fl/fl; LSL-Kras^G12D/+; Ptf1a^Cre/+ ) KPC (LSL-Kras^G12D/+; Trp53^fl/fl; Ptf1a^Cre/+ ), and AKPC (Atm^fl/fl; LSL-Kras^G12D/+; Trp53^fl/fl; Ptf1a^Cre/+ ) mouse models. Immunostainings showed that ATM and P53-deficient PDAC exhibit enriched αSMA⁺ myCAF content. Additionally, tumor cell characterization revealed that ATM-depleted cells express and secrete more TGF-β1, triggering myCAF differentiation. In contrast, ATM-proficient cell secretomes are enriched in IL1α and TNF-α, associated with iCAF phenotype. Accordingly, we found that ATM and P53 status of PDAC cells are correlated with specific CAF differentiation in vitro, notably an ATM-loss-dependent TGFβ signaling activation and overexpression of myofibroblastic markers. Finally, functional assays suggested that the genotype-specific tumor-CAF dialog is promoting tumor invasion features. Overall, our preliminary findings demonstrate that ATM and P53-depleted tumor cells are able to mediate distinct CAF differentiation, which in turn could promote tumor aggressiveness.

Publication History

Article published online:
07 September 2021