Project 1

项目1概要 肺癌中P53家族调控的代谢缺陷的鉴定 p53通常在所有人类肺癌亚型中突变。p53是一个基因家族的一部分，包括 p63和p73。p63和p73的功能开始在p53发挥作用的背景下被理解。 包括肿瘤抑制和代谢。p63和p73功能的复杂性 部分是由于存在多种异构体，以前不能在体内独立研究。充分 p63和p73的长度TA同种型含有反式激活结构域，结构和功能相似 p53，而p63和p73的ΔN同种型，虽然也具有反式激活活性，但可拮抗p53的表达。 p53的活性以及p63和p73的TA同种型。有趣的是，突变型p53，存在于各种各样的肿瘤细胞中， 人类癌症，已经显示与TAp 63和TAp 73相互作用，以抑制它们的肿瘤抑制活性。 功能这种相互作用也被证明是部分负责获得的功能活性的p53突变体。 此外，在包括非小细胞肺癌在内的许多癌症中扩增的JNP 63和JNP 73结合 并抑制p53、TAp 63和TAp 73的活性。肺癌亚型也分享了cDNA 63驱动的转录 签名（Abbas等人，Cancer Research，2017）。我们以前已经表明，p53缺陷和突变， 肿瘤可以通过代谢重编程来减少肿瘤糖酵解， 下调JNp 63或JNp 73（Venkatanarayan等人，Nature，2015; Napoli等人，Cancer Cell，2016）。 虽然我们对p53家族在癌症中的功能的认识已经扩大，但它们在肿瘤中的作用仍然是未知的。 代谢尚不清楚，p53家族成员在肺癌中调节的代谢途径 还没有被检查过。我们的首要目标是了解p53调控的代谢途径， 肺癌家族的研究，以制定针对p53突变型癌症的策略。我们已经取得了巨大的进步， 通过产生p63/p73同种型特异性条件性敲除小鼠， 每个同种型的依赖性缺失。这些工具使我们能够更深入地理解 p53家族在癌症中的相互作用。我们最近已经证明，条件性缺失的p53 Np 63， 肺腺癌的KrasG 12 D小鼠模型导致肺肿瘤负荷显著降低。 此外，我们发现KrasG 12 D/+; TAp 73 β td/β td小鼠的肺发育增加且更具侵袭性。 表型复制具有Kras和p53突变的小鼠模型的腺癌，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）小鼠模型， TAp 73，在10%的病例中发生突变。这些小鼠的表型与关键基因的变化有关。 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 定义和理解肺癌中p53家族调控的代谢途径。根据我们公布的 根据我们的工作和初步数据，我们假设，JNP 63可以下调，代谢重编程肿瘤 细胞和微环境来补偿p53功能障碍。

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.