The TGFÃÂÃÂÃÂò Signaling Pathway in Development and Cancer

发育和癌症中的 TGF 信号通路

• 批准号: 10473733
• 负责人: JOAN MASSAGUE
• 金额: $ 104.08万
• 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/10473733
• 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.

项目概要/摘要 表型可塑性及其通过背景信号的调节对于肿瘤生物学至关重要。 发育、组织稳态、再生和癌症过程中细胞表型的主要调节因子。 长期目标是阐明 TGFβ 信号传导及其对正常细胞和肿瘤细胞影响的原理。 该提案基于我们长期以来对 TGFβ 信号转导途径的贡献， 其背景依赖性效应及其在肿瘤发生和转移中的异常活性。 建立在了解 TGFβ 激活的 SMAD 转录因子如何调节的最新进展的基础上 干细胞和祖细胞的分化（Aragón et al Genes Dev. 2019；Wang et al Cell Stem Cell 2017） TGFβ 介导的肿瘤抑制和逃避这种效应的基础（David 等人 Cell 2016；Huang 等人 Cancer Disc. 2019），以及开发休眠转移的实验模型以揭示其作用 TGFβ 在癌症的这一鲜为人知但非常重要的方面（Malladi et al Cell 2016）。 最近阐明了 TGFβ 如何触发胰腺导管中的上皮间质转化（EMT） 腺癌 (PDA)、肺腺癌 (LUAD) 和胚胎干 (ES) 细胞，以及这些细胞如何 表型可塑性事件与纤维发生或分化相关，具体取决于表观遗传 基于这些进展和独特的实验模型和人类肿瘤（Su et al Nature 2019）。 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： TGFβ信号如何在发育和癌症中调节上皮细胞可塑性？ 肿瘤发生过程中TGFβ诱导的瘤内纤维化的机制是什么？ TGFβ 是如何驱动转移起始细胞进行 EMT 相关生长的？ 这种状态是否会使癌细胞在转移休眠期间逃避免疫？ 这些问题，我们将剖析一个不起眼的 RAS 效应子 RREB1，我们最近将其确定为关键合作伙伴 TGFβ 激活的 SMAD 转录因子在诱导纤维化和发育性 EMT 中的作用 阐明 EMT 相关的肿瘤内纤维化在肿瘤生长和转移中的作用。 启动细胞，我们将遵循最近的证据，表明 TGFβ 会施加一种静止的、免疫逃避的状态，从而提供 休眠转移细胞的长期存活和潜在的耐药性免疫疗法。 研究将为描述 TGFβ 在纤维化、肿瘤侵袭中的作用提供知识和实验模型 和转移，并将更好地确定如何以及何时针对癌症中的 TGFβ 进行靶向治疗。