Ecology and Evolution of Breast Carcinogenesis

翻译后摘要：在早期乳腺癌的发生，肿瘤细胞生长在多层对管腔的导管， 其使外腔细胞经受低氧、低pH和营养缺乏的恶劣条件。 适应这些苛刻的条件是早期肿瘤细胞存活的先决条件。适应性最初 急性和可逆的，但最终达尔文的选择结果与硬连线表型的细胞。一个突出 这方面的例子是有氧糖酵解，或瓦尔堡效应（WE），其中细胞是硬连线发酵 葡萄糖，即使在氧气存在的情况下。值得注意的是，WE与癌症的转移潜力高度相关。 结果不佳。因此，致癌作用中的一个主要问题是：“什么是苛刻的机制， 微环境最终选择硬连线（遗传）表型，如WE？而不是简单 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，我们结合了来自三种不同方法的联合收割机初步数据， 关于发生在癌变过程中的生态进化动力学：首先，我们对良性乳腺癌进行了研究， 癌症和上皮细胞在DCIS中遇到的恶劣条件下，并观察到存活的细胞 这些选择展示WE。我们选择了三个克隆，并应用单细胞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 所选克隆与其亲本正常细胞相比的模式。这将形成模型系统， 分析了当前的提案。在第二条调查线上，我们记录了 多发性骨髓瘤（MM）从癌前病变进展为代谢性疾病期间发生的表观遗传变化 活动性疾病。我们假设，这些观察MM可以提供一个框架，预测和解释 乳腺癌细胞从良性非糖酵解转变为侵袭性糖酵解时所经历的变化 糖酵解状态在第三条调查路线中，我们已经概述了一个连续体，从表观遗传变化开始 并展示这些是如何导致永久性突变或染色体变化的。后一项工作提供了 预测和解释微环境诱导的表观遗传变化最终如何 导致在侵袭性糖酵解乳腺癌中观察到的硬连线遗传变化。通过组合这些 方法，我们建议破译微环境胁迫诱导的基因组的机制， 进化导致了硬连线的表型适应，由WE表示。 在本研究的最后，我们期望能对这一问题有一个更完整、更全面的认识。 致癌过程中发生的环境诱导的表观遗传和遗传变化，以及这些变化之间的关系 硬连线的表型概况，作为例证的瓦尔堡效应。

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.