Investigating Max as a tumor suppressor gene in small cell lung cancer and other neuroendocrine tumors

研究 Max 作为小细胞肺癌和其他神经内分泌肿瘤的抑癌基因

• 批准号: 10601282
• 负责人: Robert Neil Eisenman
• 金额: $ 14.73万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601282
• 关键词: Investigating; Max; tumor; suppressor; gene

SUMMARY Dysregulated expression of the MYC family of transcriptional regulators is a common denominator in a wide spectrum of human cancers, including small cell lung carcinoma (SCLC), a highly aggressive neuroendocrine- type tumor that is among the leading causes of US cancer mortality. MYC family proteins specifically heterodimerize with MAX in order to bind genomic DNA and stimulate widespread transcription. Surprisingly, recent reports show that MAX is inactivated through deletions and truncating mutations in a significant subset of SCLC and other neuroendocrine cancers. The paradox that MAX may act as a tumor suppressor, but yet be crucial for MYC oncogenicity in SCLC, has important implications for our understanding of the etiology of these tumors but has not been systematically investigated. This proposal is based on the findings from our two laboratories that (i) a whole-genome CRISPR inactivation screen in pre-neoplastic SCLC (preSCs) revealed MAX-targeting sgRNAs to be highly growth promoting; and (ii) deletion of MAX dramatically accelerates SCLC in an autochthonous mouse model. These results provide, for the first time, highly relevant biological systems to elucidate MAX's tumor suppressor function. In Aim 1 we will characterize the biological properties of MAX-deleted SCLC including proliferation, apoptosis and genomic stability. Moreover, we will use ChIP-Seq and RNA-Seq to determine the genomic landscape of MYC/MYCL and MAX binding and target gene expression in SCLC and MAX-deleted SCLC. We will functionally interrogate the importance of key MAX target genes identified through integrative genomic analyses. Targets to be studied will include MAX-dependent regulators of one carbon metabolism already identified. Aim 2 is based on the hypothesis that MAX deletion not only alters MYC activity but disrupts the broader MYC- MAX transcriptional network of activators and repressors. We will determine if MYC/MYCL have MAX independent oncogenic functions in our SCLC models and in human SCLC cell lines, and examine whether network members that antagonize or cooperate with MYC (such as MXD/MNT, MLX, and MondoA), act to influence SCLC progression. In Aim 3 we propose to determine core MAX-regulated genes and pathways common to neuroendocrine tumor suppression by MAX. This will entail molecular and genetic characterization of our new models of thyroid medullary carcinomas and pheochromocytomas resulting from MAX loss (in an Rb/p53 deficient background) and identification of pathways shared with MAX-null SCLC. This research will extend the breadth of our studies to uncover how MAX suppresses neuroendocrine cancers. We anticipate that these studies will deepen our understanding of the complex role of the MYC network in both driving and suppressing neoplasia and identify novel tumorigenic pathways that may have the potential to serve as therapeutic targets.

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