Ecology and Evolution of Breast Carcinogenesis

乳腺癌发生的生态学和进化

• 批准号: 10553486
• 负责人: Mehdi Damaghi
• 金额: $ 40.84万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553486
• 关键词: Ecology; Evolution; Breast; Carcinogenesis

Abstract: In early breast carcinogenesis, neoplastic cells grow in multiple layers towards the lumens of ducts, which subjects the periluminal cells to harsh conditions of low oxygen, low pH, and nutrient deprivation. Adaptation to these harsh conditions is a pre-requisite for survival of incipient tumor cells. Adaptations are initially acute and reversible, but eventually Darwinian selection results in cells with hardwired phenotypes. A prominent example of this is aerobic glycolysis, or the Warburg Effect (WE), wherein cells are hard-wired to ferment glucose, even in the presence of oxygen. Notably, a WE is highly correlated with a cancer’s metastatic potential and poor outcome. Hence, a major question in carcinogenesis is: “What are the mechanisms by which a harsh microenvironment eventually selects for hard-wired (heritable) phenotypes, such as a WE?”. Rather than simply selection of pre-existing phenotypes, we contend that the microenvironment actively induces phenotypic diversity through a systematic set of epigenetic and genetic alterations. To address this question, we combine preliminary data from three different approaches that are all focused on the eco-evolutionary dynamics occurring during carcinogenesis: In the first, we have subjected benign breast cancer and epithelial cells to harsh conditions encountered in DCIS and have observed that the cells that survive these selections exhibit a WE. We selected three clones and applied single cell RNA sequencing and single cell ATAQ sequencing as well as whole exome sequencing to map the transcriptome, epigenome, and mutation patterns of the selected clones compared to their parental normal cells. This will form the model system to be analyzed throughout the current proposal. In the second line of investigation, we have documented the profound epigenetic changes that occur during progression of multiple myeloma (MM) from pre-malignant to metabolically active disease. We hypothesize that these observations in MM can provide a framework to predict and interpret the changes that breast cancer cells undergo as they transition from a benign non-glycolytic to an aggressive glycolytic state. In the third line of investigation, we have outlined a continuum starting with epigenetic changes and show how these result in permanent mutational or chromosomal changes. This latter work provides a framework with which to predict and interpret how microenvironment-induced epigenetic changes can eventually lead to hardwired genetic changes that are observed in aggressive glycolytic breast cancer. By combining these approaches, we propose to decipher the mechanisms whereby microenvironmental stress-induced genome evolution results in hard-wired phenotypic adaptations, represented by a WE. At the end this study, we expect to have a more complete and comprehensive understanding of the environmentally-induced epigenetic and genetic changes that occur during carcinogenesis, and how these relate to hard-wired phenotypic profiles, as exemplified by the Warburg Effect.

摘要：在早期乳腺癌发生过程中，肿瘤细胞向导管腔内多层生长， 使管腔周围的细胞处于低氧、低 pH 和营养匮乏的恶劣条件下。 适应这些严酷的条件是初期肿瘤细胞生存的先决条件。 急性和可逆的，但最终达尔文选择导致细胞具有显着的表型。 这方面的例子是有氧糖酵解，或瓦伯格效应（WE），它维持细胞天生就可以发酵 值得注意的是，WE 与癌症的转移潜力高度相关。 因此，致癌的一个主要问题是：“严酷的机制是什么？” 微环境最终会选择硬连线（可遗传）的表型，例如 WE？”。 选择预先存在的表型，我们认为微环境积极诱导表型多样性 通过一系列系统的表观遗传和遗传改变。 为了解决这个问题，我们结合了三种不同方法的初步数据，这些方法都侧重于 关于致癌过程中发生的生态进化动力学：首先，我们对良性乳房进行了研究 癌细胞和上皮细胞经历了 DCIS 中遇到的恶劣条件，并观察到存活下来的细胞 这些选择展示了 WE。我们选择了三个克隆并应用了单细胞 RNA 测序和单细胞。 ATAQ 测序以及全外显子组测序以绘制转录组、表观基因组和突变图谱 所选克隆与其亲代正常细胞相比的模式，这将形成模型系统。 在第二行调查中，我们对当前的提案进行了全面分析，记录了深刻的内容。 多发性骨髓瘤 (MM) 从癌前进展到代谢过程中发生的表观遗传变化 我们追求 MM 中的这些观察结果可以提供一个预测和解释的框架。 乳腺癌细胞从良性非糖酵解细胞转变为侵袭性细胞时所经历的变化 在第三组研究中，我们概述了从表观遗传变化开始的连续体。 并展示这些如何导致永久性突变或染色体变化。后一项工作提供了一种方法。 预测和解释微环境诱导的表观遗传变化最终如何发生的框架 通过结合这些，导致在侵袭性糖酵解乳腺癌中观察到的硬连线遗传变化。 方法，我们建议破译微环境应激诱导基因组的机制 进化导致了硬连线的表型适应，以 WE 为代表。 在本次研究结束时，我们希望对这个问题有一个更完整、更全面的了解。 致癌过程中环境引起的表观遗传和遗传变化，以及它们之间的关系 硬连线的表型特征，如瓦尔堡效应所示。