DEFINING HOW COOPERATION BETWEEN TUMOR SUBPOPULATIONS PROMOTES TUMOR PROGRESSION

定义肿瘤亚群之间的合作如何促进肿瘤进展

• 批准号: 10012774
• 负责人: Gray W Pearson
• 金额: $ 35.38万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012774
• 关键词: Address; Behavior; Benign; Blood; Breast Cancer Cell; Breast Cancer Patient; Cell Communication; Cells; Cessation of life; Clonal Expansion; Connective Tissue; Data; Development; Disease; Disease Progression; Distant Metastasis; Epigenetic Process; Evolution; Extracellular Matrix; Gene Expression; Goals; Growth; Heterogeneity; Image; In Vitro; Invaded; Investigation; Knowledge; Malignant - descriptor; Malignant Neoplasms; Metastatic to; Methods; Minority; Modeling; Neoplasm Metastasis; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Phenotype; Population; Population Dynamics; Primary Neoplasm; Process; Property; Risk; Ships; Siblings; Signal Pathway; Signal Transduction; Stream; System; Techniques; Testing; Therapeutic Intervention; Time; Translating; Tumor Cell Invasion; Variant; behavior influence; cell community; cell motility; cohesion; fitness; improved; in vivo; lung colonization; malignant breast neoplasm; neoplastic cell; novel; outcome forecast; predictive tools; prognostic; prognostic tool; programs; public health relevance; targeted treatment; therapy resistant; transcription factor; tumor; tumor heterogeneity; tumor progression

Understanding how intratumor phenotypic heterogeneity promotes disease progression is essential to improve patient care. In this proposal we focus on the cooperative relationships between distinct tumor subpopula- tions, which are a critical yet poorly understood property of heterogeneity within tumors. We have recently uncovered a new symbiotic relationship between tumors subpopulations that promotes a transition from be- nign to malignant growth by inducing the collective invasion of cohesive groups of cells. Through analysis of the intrinsic heterogeneity within cell communities, we discovered an epigenetically distinct subpopulation of breast cancer “trailblazer” cells that has an enhanced ability to initiate collective invasion. Importantly, sibling “opportunist” cells can invade through paths in the ECM created by a minority subpopulation of trailblazer cells. This democratization of invasive behavior through subpopulation cooperation eliminates a bottleneck in tumor evolution, thus unleashing the metastatic potential of a more diverse tumor cell population. We have begun uncovering components of a unique multi-gene regulatory program that is specifically required for trail- blazer cell induced collective invasion and found evidence that it is active in patients with shorter survival times. Thus, we have revealed that the activation of a new signaling network in a subpopulation of cells can induce the formation of a novel cooperative relationship that yields widespread collective invasion and has the potential to negatively impact patient survival. Defining factors that control this new “trailblazer” regulatory program and determining precisely how the interaction between trailblazer and opportunist cells contributes to cancer progression is necessary to explain how cooperative invasive behavior influences patient prognosis and reveal treatment options. Our overall objective in this proposal is to define how trailblazer and opportunist subpopulations influence tumor development. Our central hypothesis is that slow-cycling trailblazer cells in- duce metastasis by promoting the opportunistic invasion of a distinct subpopulation of metastasis initiating cells that lacks autonomous invasive ability. We will test our hypothesis and accomplish our objectives by: (1) defining factors that control the conversion between opportunist and trailblazer states; (2) determining how induction of the trailblazer state influences cell autonomous fitness and (3) determining how the cooperative relationship established between trailblazer and opportunist subpopulations contributes to metastasis. From our investigation, we expect to determine a new way in which heterogeneity promotes tumor development by revealing how the cancer hallmarks of proliferation and autonomous invasion can be distributed across distinct populations and shared in a synergistic relationship that promotes disease progression. These findings will support the development of a new mode of prognostic analysis directed towards identifying the presence and close spatial proximity of unique tumor cell subtypes. Deconstruction of processes that confer invasive ability through intercellular interactions may also uncover novel ways to thwart invasion.

了解肿瘤内表型异质性如何促进疾病进展对于改善疾病的发展至关重要 病人护理。在此提案中，我们着重于不同的肿瘤亚种之间的合作关系 这是肿瘤中异质性的关键但不了解的特性。我们最近有 发现了肿瘤亚群之间的新的共生关系，从而促进了从 通过诱导粘性细胞的集体侵袭与恶性生长。通过分析 细胞群落内的内在异质性，我们发现 乳腺癌“开拓者”细胞具有增强的启动集体入侵能力。重要的是，兄弟姐妹 “机会主义者”细胞可以通过少数群体的开拓者群体侵入ECM中的路径 细胞。通过亚群合作对侵入性行为的民主化消除了瓶颈 肿瘤的演化，从而释放了更多样化的肿瘤细胞群体的转移潜力。我们有 开始发现独特的多基因监管程序的组件，该计划是专门为TRAIL所需的 西装外套诱导的集体入侵，发现其活性在较短生存的患者中 时代。这就是我们已经揭示了细胞亚群中新信号网络的激活可以 诱导形成一种新型合作关系，该关系产生宽度的集体入侵，并具有 对患者生存产生负面影响的潜力。定义控制这种新“开拓者”监管的因素 程序并确切地确定开拓者与机会主义细胞之间的相互作用如何有助于 癌症进展是必须解释合作行为如何影响患者提示和 揭示治疗选择。我们在此提案中的总体目标是定义开拓者和选择者如何 亚群会影响肿瘤的发展。我们的中心假设是慢速循环开拓者细胞中 通过促进对转移的明显亚群的机会性入侵引发的转移 缺乏自主侵入性能力的细胞。我们将通过：（1）来检验我们的假设并实现我们的目标 定义控制机会主义和开拓者国家之间转换的因素； （2）确定如何 开拓者状态的诱导会影响细胞自主健身，（3）确定合作社如何 开拓者和机会主义亚种群之间建立的关系有助于转移。从 我们的投资，我们希望确定一种新的方式，在这种方式中，异质性通过 揭示如何将增殖和自主入侵的癌症标志分布在不同 人口并以协同关系促进疾病进展。这些发现会 支持开发一种新的预后分析模式，旨在确定存在和 独特的肿瘤细胞亚型的紧密空间接近度。解构该过程会议侵入能力 通过细胞间相互作用也可能会发现挫败入侵的新方法。