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

共济失调毛细血管扩张突变激酶 (Atm) 的时空缺失可剖析胰腺癌异质性

• 批准号: 452061284
• 负责人: Dr. Lukas Perkhofer
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/452061284?language=en
• 关键词: Spatio; temporal; deletion; Ataxia; telangiectasia

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.

胰腺导管腺癌(PDAC)是发生在胰腺的最常见的癌症类型，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生物学的了解正在稳步增加，一些里程碑式的研究因此证明了有价值的基因工程小鼠模型(GEMM)。PDAC的特点是具有广泛的遗传异质性，具有少数驱动突变和过多的乘客突变(例如ATM、BRCA1/2)。共济失调-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，它磷酸化了许多参与细胞周期停滞、DNA修复和细胞凋亡的关键蛋白。大规模测序分析已经在8%到18%的人类PDAC队列中发现了ATM突变，甚至可以在某些个体的生殖系中检测到这种突变。我之前的工作揭示了在使用条件性ATM基因敲除小鼠的PDAC开发中ATM丢失的功能后果。具体地说，我发现了更多的前驱病变和高度侵袭性的PDAC亚型，伴随着加速的上皮向间充质转变(EMT)，基因组不稳定以及ATM丢失后间质含量的增加。此外，我在ATM缺陷的PDAC中识别了合成的致命靶点，从而揭示了针对这类患者的新的治疗策略。作为这些收集到的知识的合乎逻辑的结果，目前的提案旨在通过破译ATM在维持胰腺中相对于细胞间隔的基因组完整性方面的作用来理解ATM如何促进癌症的形成。此外，我想研究在没有致癌KRAS的情况下胰腺异型增生的触发因素，例如炎症。具体地说，我的目的是阐明胰腺中最允许的细胞类型在有条件的和可诱导的ATM丧失后变得异常发育。因此，我计划描述和描述由于(I)腺泡、(Ii)导管或(Iii)胰腺干细胞在存在或不存在炎症的情况下特定的ATM耗竭而产生的潜在的肿瘤表型。总而言之，目的是阐明在胰腺癌发生过程中，ATM在微环境改变中所起的细胞类型特异性作用。