The TGFÃÂÃÂÃÂò Signaling Pathway in Development and Cancer

项目摘要/摘要 表型可塑性及其受环境信号的调节对肿瘤生物学具有重要意义。转化生长因子β是 是发育、组织动态平衡、再生和癌症过程中细胞表型的主要调节因子。我们的长- 学期目标是阐明转化生长因子β信号及其对正常细胞和肿瘤细胞影响的原理。 这一建议是基于我们长期以来对描绘转化生长因子β信号转导途径的贡献， 它的上下文依赖效应，以及它在肿瘤发生和转移中的异常活性。拟议中的工作 建立在了解转化生长因子β激活的SMAD转录因子如何调控的最新进展基础上 干细胞和祖细胞的分化(Aragón等人基因开发。2019年；Wang等人细胞干细胞2017)，The 转化生长因子β介导的肿瘤抑制的基础和这一效应的规避(David等人细胞2016；Huang等人 癌症光盘。2019)，以及发展隐匿转移的实验模型以揭示其作用 转化生长因子β在这一知之甚少但意义重大的癌症方面(Malladi等人细胞2016)。此外，我们 最近阐明转化生长因子β如何触发胰腺导管上皮-间充质转化(EMT) 腺癌(PDA)、肺腺癌(LUAD)和胚胎干细胞(ES)，以及它们是如何 表型可塑性事件与纤维形成或分化有关，这取决于表观遗传学。 上下文(Su等人，《自然》，2019)。基于这些进展和独特的实验模型与人类肿瘤 通过我们开发的单细胞分析，我们将解决日益重要的长期存在的问题： 转化生长因子β信号如何在发育和癌症中调节上皮细胞的可塑性？这个角色是什么？ 转化生长因子β诱导的肿瘤内纤维化在肿瘤发生中的作用？这一机制的相关性是什么 对转化生长因子β诱导的器官纤维化有何影响？转化生长因子β如何驱动肿瘤转移起始细胞进入EMT相关生长 逮捕？这种状态是否使癌细胞在转移休眠期间免疫逃避？去调查 这些问题，我们将剖析一个鲜为人知的RAS效应器，RREB1，我们最近确定它是一个关键合作伙伴 转化生长因子β激活的SMAD转录因子在诱导纤维化和发育性子宫内膜样变中的作用。我们会 阐明EMT相关的肿瘤内纤维化在肿瘤生长和转移中的作用。专注于转移- 启动细胞，我们将跟踪最近的证据，转化生长因子β强加一种静止的，免疫逃避状态，提供 对处于休眠状态的转移细胞的长期存活和潜在的抵抗免疫治疗。总而言之，这些 研究将提供知识和实验模型来描述转化生长因子β在纤维化、肿瘤侵袭中的作用。 并将更好地定义在癌症中靶向转化生长因子β的方式和时间。

PROJECT SUMMARY/ABSTRACT Phenotypic plasticity and its regulation by contextual signals is of central importance to tumor biology. TGFβ is a major regulator of cell phenotype during development, tissue homeostasis, regeneration, and cancer. Our long- term goal is to elucidate TGFβ signaling and the principles that govern its effects on normal and neoplastic cells. This proposal is based on our long-standing contributions to delineating the TGFβ signal transduction pathway, its context-dependent effects, and its aberrant activity in tumorigenesis and metastasis. The proposed work builds on recent progress towards understanding how TGFβ-activated SMAD transcription factors regulate differentiation in stem and progenitor cells (Aragón et al Genes Dev. 2019; Wang et al Cell Stem Cell 2017), the basis for TGFβ-mediated tumor suppression and the evasion of this effect (David et al Cell 2016; Huang et al Cancer Disc. 2019), and the development of experimental models of dormant metastasis to expose the role of TGFβ in this poorly understood, yet highly significant aspect of cancer (Malladi et al Cell 2016). Moreover, we recently elucidated how TGFβ triggers epithelial-mesenchymal transitions (EMTs) in pancreatic ductal adenocarcinoma (PDA), lung adenocarcinoma (LUAD), and embryonic stem (ES) cells, and how these phenotypic plasticity events are coupled either to fibrogenesis or to differentiation depending on the epigenetic context (Su et al Nature 2019). Based on these advances and unique experimental models and human tumor single-cell analytics that we have developed, we will address long-standing questions of growing importance: How does TGFβ signaling regulate epithelial cell plasticity in development and cancer? What is the role of TGFβ-induced intra-tumoral fibrosis during tumorigenesis? What is the relevance of this mechanism to TGFβ-induced organ fibrosis? How does TGFβ drive metastasis-initiating cells into EMT-linked growth arrest? Does this state render cancer cells immune-evasive during metastasis dormancy? To investigate these questions, we will dissect an obscure RAS effector, RREB1, which we recently identified as a key partner of TGFβ-activated SMAD transcription factors in the induction of fibrogenic and developmental EMTs. We will elucidate the role of EMT-linked intra-tumoral fibrosis in tumor growth and metastasis. Focusing on metastasis- initiating cells, we will follow recent evidence that TGFβ imposes a quiescent, immune evasive state that provides long-term survival to dormant metastasis cells and potentially resistance immunotherapy. Collectively, these studies will provide knowledge and experimental models to delineate the role of TGFβ in fibrosis, tumor invasion and metastasis, and will better define how and when to target TGFβ in cancer.