DEFINING HOW COOPERATION BETWEEN TUMOR SUBPOPULATIONS PROMOTES TUMOR PROGRESSION

了解肿瘤内表型的异质性如何促进疾病进展是改善疾病的关键 病人护理。在这项建议中，我们关注不同的肿瘤亚群之间的合作关系- 这是肿瘤内异质性的一个关键但知之甚少的属性。我们最近做了 发现了一种新的肿瘤亚群之间的共生关系，促进了从BE-BE到BE-BE的转变 通过诱导凝聚在一起的细胞群的集体入侵来阻止恶性生长。通过对……的分析 细胞群落内的内在异质性，我们发现了一个表观遗传上截然不同的亚群 乳腺癌“开拓者”细胞具有更强的集体侵袭能力。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造的ECM路径入侵 细胞。这种通过亚种群合作实现的入侵行为民主化消除了 肿瘤进化，从而释放更多样化的肿瘤细胞群的转移潜力。我们有 开始揭示一种独特的多基因调控程序的组成部分，这是TRAIL- Blazer细胞诱导集体侵袭，发现有证据表明它在生存期较短的患者中是活跃的 泰晤士报。因此，我们揭示了在一个细胞亚群中新的信号网络的激活可以 诱导形成一种新的合作关系，产生广泛的集体入侵，并具有 有可能对患者的生存产生负面影响。定义控制这一新的“开拓者”监管的因素 规划并准确确定开拓者和机会主义细胞之间的互动如何有助于 癌症进展是必要的，以解释合作侵袭行为如何影响患者预后 展示治疗方案。我们在这项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周期的开拓者细胞- 通过促进不同转移亚群的机会性侵袭来启动转移 缺乏自主侵袭能力的细胞。我们将通过以下方式验证我们的假设并实现目标：(1) 定义控制机会主义者和开拓者状态之间转换的因素；(2)确定如何 开拓者状态的诱导影响细胞自主适应和(3)决定如何合作 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，我们希望通过以下方式确定异质性促进肿瘤发展的新方式 揭示了增殖和自主侵袭的癌症特征如何分布在不同的 并在促进疾病进展的协同关系中共享。这些发现将 支持开发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。解构赋予侵入性能力的过程 通过细胞间的相互作用也可能发现阻止入侵的新方法。

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.