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

胰腺导管腺癌（PDAC）是胰腺中最常见的癌症类型，也是发达国家癌症死亡的第四大原因。最近的预测表明，到2030年，PDAC将超过乳腺癌、前列腺癌和结肠直肠癌，成为癌症相关死亡的第二大原因。与此同时，我们对PDAC生物学的理解也在稳步增长，一些具有里程碑意义的研究也因此证明了有价值的基因工程小鼠模型（GEMMs）。PDAC的特点是具有广泛的遗传异质性，具有少量驱动突变和过多的乘客突变（例如ATM， BRCA1/2）。ataxia -毛细血管扩张突变（ATM）是一种丝氨酸/苏氨酸蛋白激酶，作用于P53的上游，磷酸化许多参与细胞周期阻滞、DNA修复和凋亡的关键蛋白。大规模测序分析已经在8%至18%的人类PDAC群体中发现了ATM突变，甚至可以在某些个体的种系中检测到。我以前的工作已经揭示了ATM丢失在PDAC开发中的功能后果，使用条件ATM敲除小鼠。具体来说，我发现更多的前体病变和高度侵袭性的PDAC亚型，具有加速的上皮到间质转化（EMT），基因组不稳定以及在atm丢失时基质含量增加。此外，我在atm缺陷PDAC中发现了合成致死靶点，从而为这类患者揭示了新的治疗策略。作为这些收集到的知识的一个合乎逻辑的结果，目前的建议旨在通过破译其在胰腺中相对于细胞区维持基因组完整性的作用来了解Atm如何促进癌症的形成。此外，我想研究在没有致癌KRAS（如炎症）的情况下胰腺发育不良的触发因素。具体来说，我的目标是阐明胰腺中最容易在条件和诱导的atm丢失时变得发育不良的细胞类型。因此，我计划描述和表征在存在或不存在炎症的情况下，胰腺中(I)腺泡细胞、（ii）导管细胞或（iii）干细胞中特异性atm耗竭所引起的强有力的肿瘤表型。总之，目的是阐明ATM在胰腺癌发生过程中微环境改变方面的细胞类型特异性作用。

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.