Spatio-temporal deletion of the Ataxia-telangiectasia mutated kinase (Atm) to dissect pancreatic cancer heterogeneity

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Pancreatic ductal adenocarcinoma (PDAC) is the most common type of cancer arising in the pancreas and the fourth leading cause of cancer death in the developed world. Recent predictions suggest that PDAC will surpass breast, prostate, and colorectal cancer to become the second leading cause of cancer-related death by 2030. Meanwhile, our understanding of PDAC biology has steadily increased, and several landmark studies have demonstrated valuable genetically engineered mouse models (GEMMs) therefore. PDAC is characterized by a broad genetic heterogeneity with a handful of driver mutations and a plethora of passenger mutations (e.g. ATM, BRCA1/2). Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase, acting upstream of P53, that phosphorylates many key proteins involved in cell cycle arrest, DNA repair, and apoptosis. Large-scale sequencing analysis have identified ATM mutations in 8 to 18% of human PDAC cohorts, which can be even detected in the germline of certain individuals. My previous works have revealed the functional consequences of ATM loss in PDAC development using conditional Atm-knock out mice. Specifically, I found more precursor lesions and a highly aggressive PDAC subtype with an accelerated epithelial-to-mesenchymal transition (EMT), genomic instability as well as an increased stromal content upon Atm-loss. In addition, I identified synthetically lethal targets in Atm-defective PDAC, thus revealing novel therapeutic strategies for such patients. As a logical consequence of this gathered knowledge, the current proposal aims to understand how Atm promotes cancer formation by deciphering its role of maintaining genome integrity in the pancreas relative to the cellular compartment. Moreover, I would like to study the triggers of pancreatic dysplasia in the absence of oncogenic KRAS such as inflammation. Specifically, I aim to elucidate the most permissive cell type in the pancreas to become dysplastic upon conditional and inducible Atm-loss. Hence, I plan to describe and characterize the potent tumor phenotypes arising from specific Atm-depletion in either (i) acinar, (ii) ductal, or (iii) stem cells in the pancreas in the presence or absence of inflammation. In summary, the purpose is to shed light on the cell type specific role of ATM in terms of an altered microenvironment during pancreatic carcinogenesis.