Mechanisms in Cancer Evolution Program

癌症进化机制计划(MCEP) 项目总结 DLDCCC癌症进化机制计划(MCEP)的任务重点是 了解产生异质性的分子机制(遗传和非遗传或表观遗传)和 刺激癌症进化的环境驱动因素。进化是通过变异发生的，变异创造了异质性 和选择。异质性是由固有的基因组和非遗传的表型-可塑性产生的 机制，以及通过外源病毒、微生物组和营养改变细胞程序 调制。MCEP的目标是基础科学发现这些分子机制是如何 工作。发现的新范例可以开辟新的翻译方向(在整个DLDCCC计划和 其他人)，包括新的进化生物标记物、诊断、预防和治疗工具。例如, 虽然传统疗法杀死细胞或阻止它们生长(具有抗增殖作用)，但提出的新方法 将减缓进化的干预措施，承诺以新的和根本不同的方式抑制肿瘤发生 并挫败抵抗。此外，识别高度进化的细胞的生物标记物可能允许检测风险 个人，以及癌症的早期检测。MCEP目前有26个成员：25个是研究成员 来自分子和人类遗传学、分子病毒学和微生物学的BCM系， 生物化学和分子生物学、儿科-肿瘤学、医学-传染病、病理学和 免疫学和赫芬顿老龄中心；其中一人是兼职成员，由华盛顿大学任命 德克萨斯州，奥斯汀。MCEP成员在之前的资助中共发表了576篇与癌症有关的论文 影响因子为10或以上的期刊占25%。在576篇手稿中，11%代表内部 方案、46%的方案间和68%的机构间协作。MCEP目前有一个 选定的与癌症有关的资金(每年的直接费用)共计1050万美元，其中包括来自 NCI，580万美元的其他NIH资金和220万美元的其他同行审查资金，主要来自癌症 得克萨斯州预防和研究倡议(CPRIT)。MCEP的两个目标包括以下机制 通过以下方式促进异质性：(1)内在进化启动子(突变、基因组重排、 重组、表观遗传可遗传蛋白质和RNA错误介导的变异)；以及(2)外在进化 启动子，包括病毒、微生物、微生物组和寄主和营养调节剂 微生物组。CCSG通过提供关键共享资源来支持该研究计划，特别是 参数流式细胞术；先进显微镜和图像信息学；基因组学，转录学， 表观基因组学和单细胞、代谢组学和蛋白质组学；以及会议的行政支持， 俱乐部和利益集团，以及试点资金和招募基金。

Mechanisms in Cancer Evolution Program (MCEP) PROJECT SUMMARY The mission of the Mechanisms in Cancer Evolution Program (MCEP) at the DLDCCC is focused on understanding molecular mechanisms that generate heterogeneity (genetic and non-genetic or epi-genetic) and environmental drivers that spur evolution of cancers. Evolution occurs by variation, which creates heterogeneity and selection. Heterogeneity is generated by intrinsic genomic and non-genetic phenotype-plasticity mechanisms, as well as by alteration of cellular programs by extrinsic viruses, the microbiome, and nutritional modulation. The goal of the MCEP is fundamental basic science discovery of how these molecular mechanisms work. New paradigms discovered can open new translational directions (throughout the DLDCCC Programs and by others), including novel evolutionary biomarkers, diagnostic, preventative, and therapeutic tools. For example, whereas conventional therapies kill cells or stop them from growing (are anti-proliferative), proposed novel interventions that would slow evolution, promise new and fundamentally different ways to inhibit oncogenesis and thwart resistance. Also, identification of biomarkers of highly evolvable cells may allow detection of at-risk individuals, and earlier detection of cancers. The MCEP currently has 26 members: 25 are Research members from the BCM Departments of Molecular and Human Genetics, Molecular Virology and Microbiology, Biochemistry and Molecular Biology, Pediatrics-Oncology, Medicine-Infectious Disease, Pathology and Immunology, and the Huffington Center on Aging; one is an adjunct member, appointed at the University of Texas, Austin. Members of the MCEP published a total of 576 cancer-related papers in the previous funding period with 25% in journals with Impact Factors of 10 or above. Of the 576 manuscripts, 11% represented intra- programmatic, 46% inter-programmatic, and 68% inter-institutional collaborations. The MCEP currently has a total of $10.5 million in selected cancer-relevant funding (direct costs per annum), which includes $2 million from NCI, $5.8 million in other NIH funding and $2.2 million in other peer reviewed funding mostly from the Cancer Prevention and Research Initiative of Texas (CPRIT). The two MCEP Aims encompass mechanisms of promotion of heterogeneity by: (1) Intrinsic Evolution Promoters (mutation, genome rearrangement, recombination, epigenetic heritable protein- and RNA-error-mediated variation); and (2) Extrinsic Evolution Promoters, including viruses, microbes generally, the microbiome, and nutritional modulators of both host and microbiome. The CCSG supports this Research Program by providing key Shared Resources, particularly High- Parameter Flow Cytometry; Advanced Microscopy and Image Informatics; Genomic, Transcriptomic, Epigenomic and Single-Cell, Metabolomics, and Proteomics; as well as administrative support for meetings, clubs and interest groups, and pilot funding and recruitment funds.