Project 1

项目1总结 肺癌中受P53家族调控的代谢易损性研究 P53在人类肺癌的所有亚型中都有常见的突变。P53是一个基因家族的一部分，它包括 P63和p73。P63和P73的功能在P53发挥作用的上下文中开始被理解 已经得到了很好的证实，包括肿瘤抑制和代谢。P63和p73函数的复杂性 部分原因是存在以前不能在体内独立研究的多种异构体。饱满 长度为TA的p63和p73亚型含有一个结构和功能相似的反式激活结构域 而p63和p73的ΔN亚型虽然也具有反式激活活性，但拮抗 P53及P63、P73 TA异构体的活性。有趣的是，突变型P53，存在于各种各样的 人类癌症，已被证明与TAp63和TAp73相互作用，使其肿瘤抑制作用失活 功能。这种相互作用也被证明是获得P53突变体功能活性的部分原因。 此外，∆Np63和∆Np73在包括非小细胞肺癌在内的许多癌症中都被扩增，它们与 抑制P53、TAp63、TAp73的活性。肺癌亚型也分享∆Np63驱动的转录 签名(阿巴斯等人，癌症研究，2017年)。我们以前已经证明了P53基因缺失和突变 肿瘤可以通过代谢重新编程来减少肿瘤的糖酵解，从而导致肿瘤消退 下调∆Np63或∆Np73(Venkatanarayan等人，《自然》，2015；那不勒斯等人，《癌细胞》，2016)。 尽管我们对P53家族在癌症中的功能的了解已经扩大，但它们在肿瘤中的作用 肺癌中的代谢尚不清楚，其代谢途径受P53家族成员调控 都没有经过检查。我们的首要目标是了解受p53调控的代谢途径。 肺癌家庭制定针对p53突变癌症的策略。我们已经取得了长足的进步， 这个目标是通过产生p63/p73亚型特异的条件性基因敲除小鼠来考虑时间和上下文 每种异构体的依赖缺失。这些工具使我们获得了更大的机械性理解 P53家族在癌症中的相互作用。我们最近证明了∆Np63的有条件删除在 KrasG12D小鼠肺腺癌模型显著降低了肺癌的负担。 此外，我们还发现KrasG12D/+；TAp73TAp73Td/∆TD/∆Td小鼠出现肺增加和更具侵袭性 带有Kras和P53突变的表型复制小鼠模型的腺癌，类似于在 人类肺癌。最后，我们开发了一种新的小细胞肺癌(SCLC)缺失的小鼠模型 TAp73，在10%的病例中发生突变。这些小鼠的表型与键的变化有关 代谢途径包括糖酵解和半胱氨酸代谢。我们在此应用程序中的主要目标是 明确和了解肺癌中受P53家族调控的代谢途径。基于我们发布的 工作和初步数据，我们假设∆np63可以被下调以对肿瘤进行代谢重新编程 细胞和微环境对P53功能障碍的补偿。

PROJECT 1 SUMMARY IDENTIFYING METABOLIC VULNERABILITIES REGULATED BY THE P53 FAMILY IN LUNG CANCER p53 is commonly mutated in all subtypes of human lung cancer. p53 is part of a family of genes that includes p63 and p73. The functions of p63 and p73 are beginning to be understood in contexts in which p53 function has been well established including tumor suppression and metabolism. The complexity of p63 and p73 function is due in part to the existence of multiple isoforms that previously could not be studied independently in vivo. Full length TA isoforms of p63 and p73 contain a transactivation domain, structurally and functionally resembling p53, whereas the ΔN isoforms of p63 and p73, while also possessing transactivation activity, antagonize the activities of p53 and the TA isoforms of p63 and p73. Interestingly, mutant p53, present in a wide variety of human cancers, has been shown to interact with TAp63 and TAp73 to inactivate their tumor-suppressive function. This interaction has also been shown to be partly responsible for gain of function activity of p53 mutants. Moreover, ∆Np63 and ∆Np73, which are amplified in many cancers, including non-small cell lung cancer, bind and inhibit the activity of p53, TAp63, and TAp73. Lung cancer subtypes also share ∆Np63 driven transcriptional signatures (Abbas et al., Cancer Research, 2017). We have shown previously that p53 deficient and mutant tumors can be metabolically reprogrammed to decrease tumor glycolysis and result in tumor regression through downregulation of ∆Np63 or ∆Np73 (Venkatanarayan et al., Nature, 2015; Napoli et al., Cancer Cell, 2016). Although our knowledge on the functions of the p53 family in cancer has expanded, their roles in tumor metabolism are not understood, and the metabolic pathways regulated by the p53 family members in lung cancer have not been examined. Our overarching goal is to understand the metabolic pathways regulated by the p53 family in lung cancer to develop strategies to target p53 mutant cancers. We have made great strides toward this goal by generating p63/p73 isoform-specific conditional knockout mice to allow for temporal and context dependent deletions of each isoform. These tools have allowed us to gain a greater mechanistic understanding of the interplay of the p53 family in cancer. We have recently demonstrated that conditional deletion of ∆Np63 in the KrasG12D mouse model of lung adenocarcinoma results in dramatically decreased lung tumor burden. Additionally, we have found that KrasG12D/+;TAp73∆td/∆td mice develop increased and more aggressive lung adenocarcinomas that phenocopy mouse models with Kras and p53 mutations, similar to the ones found in human lung cancer. Lastly, we have developed a novel mouse model of small cell lung cancer (SCLC) lacking TAp73, which is mutated in 10% of cases. The phenotypes of these mice are associated with changes in key metabolic pathways including glycolysis and cysteine metabolism. Our primary objective in this application is to define and understand metabolic pathways regulated by the p53 family in lung cancer. Based on our published work and preliminary data, we hypothesize that ∆Np63 can be downregulated to metabolically reprogram tumor cells and the microenvironment to compensate for p53 dysfunction.