The TGFÃÂÃÂÃÂò Signaling Pathway in Development and Cancer

发育和癌症中的 TGF 信号通路

• 批准号: 10238832
• 负责人: JOAN MASSAGUE
• 金额: $ 106.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238832
• 关键词: Address; Cells; Coupled; Development; Epigenetic Process; Epithelial; Epithelial Cells; Event; Experimental Models; Exposure to; Fibrosis; Genes; Goals; Growth; Homeostasis; Human; Immune Evasion; Immunotherapy; Knowledge; Link; Lung Adenocarcinoma; Malignant Neoplasms; Mediating; Mesenchymal; Natural regeneration; Nature; Neoplasm Metastasis; Normal Cell; Organ; Pancreatic Ductal Adenocarcinoma; Phenotype; Regulation; Relapse; Residual Tumors; Resistance; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Tissues; Transforming Growth Factor beta; Tumor Biology; Tumor Cell Invasion; Tumor Suppression; Work; base; cancer cell; embryonic stem cell; fibrogenesis; neoplastic cell; stem cells; therapy resistant; transcription factor; tumor; tumor growth; tumorigenesis

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.

项目总结/摘要 表型可塑性及其通过背景信号的调节对肿瘤生物学具有核心重要性。TGFβ是 在发育、组织稳态、再生和癌症期间细胞表型的主要调节器。我们长久以来- 长期目标是阐明TGFβ信号传导及其对正常和肿瘤细胞作用的原理。 该提案基于我们长期以来对阐明TGFβ信号转导途径的贡献， 它的环境依赖性作用，以及它在肿瘤发生和转移中的异常活性。拟议工作 建立在对TGFβ激活的SMAD转录因子如何调节 干细胞和祖细胞的分化（Aragón等Genes Dev. 2019; Wang et al Cell Stem Cell 2017）， TGFβ介导的肿瘤抑制的基础和这种效应的逃避（大卫等人细胞2016;黄等人 癌症椎间盘2019），并开发了休眠转移的实验模型，以揭示 TGFβ在这一知之甚少但高度重要的癌症方面的作用（Malladi et al Cell 2016）。而且我们 最近阐明了TGFβ如何触发胰腺导管中的上皮-间充质转化（EMT）， 腺癌（PDA）、肺腺癌（LUAD）和胚胎干（ES）细胞，以及这些细胞是如何在肺腺癌（PDA）、肺腺癌（LUAD）和胚胎干（ES）细胞中表达的。 表型可塑性事件与纤维发生或分化相关，这取决于表观遗传学 上下文（Su et al Nature 2019）。基于这些进展和独特的实验模型和人类肿瘤 我们开发的单细胞分析，我们将解决长期存在的日益重要的问题： TGFβ信号如何调节上皮细胞在发育和癌症中的可塑性？有什么作用 肿瘤发生过程中TGFβ诱导的肿瘤内纤维化？这一机制的相关性是什么 转化生长因子β诱导的器官纤维化TGFβ如何驱动转移起始细胞进入EMT相关生长 逮捕？这种状态是否使癌细胞在转移休眠期间具有免疫逃避性？探讨 这些问题，我们将剖析一个模糊的RAS效应器，RREB 1，我们最近确定为一个关键的合作伙伴 TGFβ激活的SMAD转录因子在诱导纤维化和发育性EMT中的作用我们将 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，我们将遵循最近的证据表明，TGFβ施加一个静止的，免疫逃避状态， 长期存活休眠转移细胞和潜在的抵抗免疫疗法。总的来说，这些 研究将提供知识和实验模型，以描述TGFβ在纤维化、肿瘤侵袭、 和转移，并将更好地定义如何以及何时在癌症中靶向TGFβ。