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: 10247474
• 负责人: Gray W Pearson
• 金额: $ 34.73万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247474
• 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; Prognosis; 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; 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 病人护理在这个建议中，我们专注于不同的肿瘤亚群之间的合作关系， 这是肿瘤内异质性的关键但知之甚少的性质。我们最近 揭示了肿瘤亚群之间的一种新的共生关系，这种关系促进了从 通过诱导粘性细胞群的集体侵入而导致恶性生长。通过分析 细胞群落内的内在异质性，我们发现了一个表观遗传学上不同的亚群， 乳腺癌“开拓者”细胞，具有增强的启动集体入侵的能力。重要的是，兄弟姐妹 “机会主义”细胞可以通过由少数开拓者亚群创建的ECM中的路径侵入 细胞这种通过亚群合作的入侵行为的民主化消除了一个瓶颈， 肿瘤演变，从而释放更多样化的肿瘤细胞群的转移潜力。我们有 开始发现一个独特的多基因调控程序的组成部分，这是特别需要的线索， blazer细胞诱导集体侵袭，并发现证据表明，它在生存期较短的患者中很活跃 次因此，我们已经揭示了在细胞亚群中激活一个新的信号网络， 诱导形成一种新的合作关系，产生广泛的集体入侵， 可能对患者生存产生负面影响。定义控制这一新的“开拓者”监管的因素 计划和精确确定开拓者和机会主义细胞之间的相互作用如何有助于 癌症进展是必要的，以解释合作侵入行为如何影响患者预后， 显示治疗方案。我们在这个提案中的总体目标是定义开拓者和机会主义者 亚群影响肿瘤的发展。我们的中心假设是慢循环的先驱细胞- 通过促进不同转移起始亚群的机会性侵袭来诱导转移， 缺乏自主入侵能力的细胞。我们将测试我们的假设和实现我们的目标：（1） 确定控制机会主义国家和开拓者国家之间转换的因素;（2）确定如何 诱导的开拓者状态影响细胞自主适应性和（3）确定如何合作 开拓者和机会主义者亚群之间建立的关系有助于转移。从 我们的研究，我们希望确定一种新的方式，异质性促进肿瘤的发展， 揭示了增殖和自主入侵的癌症标志如何在不同的细胞中分布， 人群，并在促进疾病进展的协同关系中共享。这些发现将 支持发展一种新的预后分析模式，以确定是否存在和 独特的肿瘤细胞亚型在空间上非常接近。破坏赋予侵入能力的过程 通过细胞间的相互作用也可能揭示新的方法来阻止入侵。