ATM and P53 autonomous roles during pancreatic cancer tumorigenesis

Despite intensive efforts in basic and translational research, pancreatic ductal adenocarcinoma (PDAC) still has a dismal prognosis. ATM, involved in homologous recombination (HR), is the most frequently mutated DNA damage repair (DDR) gene in PDAC. We previously showed that the loss of ATM accelerates PDAC formation and favors mesenchymal phenotype. ATM inactivation also generates a HR deficiency mimicking human unstable PDAC subtype, rendering tumor cells more sensitive to DNA damaging drugs. Interestingly, a P53 stabilization was observed in ATM-deficient tumors suggesting a response to genomic instability. The loss of P53, which acts downstream ATM during DDR, is known to trigger drug resistance and aggressive phenotype. However, the molecular implications associated with the loss of ATMand/or TP53in PDAC remain elusive.We suggest that the loss of P53 in combination with ATM deficiency might lead to the development of more aggressive and resistant PDAC. Thus, to decipher the molecular and phenotypic effects resulting from their combined losses, we crossed LSL-Kras^G12D mice with Atm^fl/fl and Trp53^fl/fl knockout mice.

Initial data showed a reduced survivalinAtm^fl/fl; Trp53^fl/fl; LSL-Kras^G12D/+; Ptf1a^Cre/+ (AKPC) mice, associated with higher metastasis rates. Immunostainings revealed that the loss of ATM in P53-depleted context correlated with an increased number of high-grade PanIN lesions, acinar-to-ductal metaplasia, and extensive fibrosis. In line, AKPC cells showed greater migratory abilities. Moreover, ATM loss led to a pronounced accumulation of double-strand breaks and aneuploidy reflecting a high level of genomic instability in AKPC cells. We also revealed that, even in the drug-resistant P53-deficient context displaying apoptosis abrogation, ATM loss generates HR deficiency and creates targetable susceptibilities to DNA damaging drugs. The presence of morphological signs as micronuclei and multinucleated cells suggest a mitotic catastrophe-mediated cell death.

Our findings revealed that ATM and P53 exert autonomous roles during tumor progression, explaining the higher aggressivity of co-depleted tumors. Finally, we demonstrated that ATM deficiency generates specific molecular patterns and workable vulnerabilities, even in P53-deficient tumors.

Publikationsverlauf

Artikel online veröffentlicht:
07. September 2021