Exploring roles of ATM-deletion in pancreatic cancer vulnerabilities and cancer-associated fibroblast/tumor cell crosstalk

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the Western World. Recent sequencing studies found ATM serine/threonine kinase (ATM) frequently mutated in PDAC. Our laboratory previously showed that the loss of ATM accelerates EMT and promotes genomic instability in an oncogenic KRAS^G12Dcontext (Atm^fl/fl; Kras^G12D; p48^Cre, AKC). We could identify a new targeted and synergistic route to reach highest efficiency with lowest toxicity by allowing synthetic lethality in ATM-deficient PDAC patients (PARP/ATR/DNA-PK inhibition; Gout, Perkhofer, in revision). Surprisingly, a stabilization of P53 was observed in AKC tumors suggesting a response to genomic instability that could slow down the tumorigenesis. Because PDAC displaying both TP53 and ATM mutations represent a subtype that could be more resistant to DNA damaging treatment, we studied the effect of P53 KO in an Atm-deleted context. For that, we generated an Atm^fl/fl; Trp53^fl/fl; Kras^G12D; p48^Cre(APKC) mouse model displaying a shortened survival. A drug screening showed that responsiveness of AKPC cells to DNA damaging drugs is reduced. As well, the efficiency of our PAD therapy was decreased when applied on APKC cells, proving that PAD-induced apoptosis in AKC cells was at least partially mediated by P53 and highlighting that TP53 status should be verified before considering a treatment with DNA damaging agents. In parallel, systematic characterization of pancreatic tumors and isolated tumor cells revealed the more mesenchymal phenotype of APKC cells. Interestingly, cancer-associated fibroblasts (CAFs) content of APKC tumors also differs when compared to other tumors as shown by the higher proportion of inflammatory CAFs present in APKC tumors. This suggests a putative role of this CAF subpopulation in the development of the aggressive ATM^KO/P53^KOphenotype. Trying to decipher the role of ATM deficiency in tumor phenotype and in CAF/tumor crosstalk, we performed a protein array on tumor cell conditioned medium which found that APKC cells effectively secrete more inflammatory factors. To summarize, preliminary data provided first evidence that ATM status could play a role in switching CAF phenotype which in turn could dramatically promote tumor aggressiveness.

Publication History

Article published online:
08 September 2020