Role of Type III TGF-beta Receptor Shedding in Lung Cancer Initiation and Progression

III 型 TGF-β 受体脱落在肺癌发生和进展中的作用

• 批准号: 9030939
• 负责人: Jennifer J Huang
• 金额: $ 4.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030939
• 关键词: Address; Adenocarcinoma Cell; Apoptosis; Base Pairing; Binding; Biological; Cancer Biology; Cancer Etiology; Cancer Patient; Cathepsin G; Cell Cycle Regulation; Cell Line; Cell Surface Receptors; Cell surface; Cessation of life; Cleaved cell; Conditioned Culture Media; Consensus; Data; Development; Diagnosis; Disease; Disease Progression; Disintegrins; Elastases; Exhibits; Family; Female; Generations; Genetically Engineered Mouse; Human; Immune; Immune response; Immune system; In Vitro; Lead; Ligands; Literature; Lung Adenocarcinoma; MMP2 gene; MMP9 gene; Malignant Neoplasms; Malignant neoplasm of lung; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Messenger RNA; Metalloproteases; Modeling; Molecular; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Peptide Hydrolases; Production; Proteins; Recombinant Proteins; Recombinants; Regulation; Role; Signal Pathway; Signal Transduction; Site; Specificity; System; TGF beta type III receptor; Therapeutic; Therapeutic Agents; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Tumor Promoters; Tumor Suppressor Proteins; Tumorigenicity; Work; advanced disease; angiogenesis; base; cancer cell; cancer diagnosis; cancer initiation; carcinogenesis; cell growth; cell motility; gain of function; in vivo; inhibitor/antagonist; insight; lung Carcinoma; male; member; migration; mouse model; mutant; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; receptor; restoration; small hairpin RNA; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Transforming growth factor-ß (TGF-ß) is involved in many aspects of cancer biology, including proliferation, apoptosis, migration, and metastasis. TGF-ß's effects are mediated through a family of cell surface receptors, including the type III TGF-ß receptor (TßRIII), which can mediate downstream signaling. TßRIII is lost in many human cancers, including non-small cell lung cancer (NSCLC), with loss correlated with more aggressive disease and disease progression. TßRIII also undergoes ectodomain cleavage, producing a soluble protein (sTßRIII) that may sequester ligand away from the cell surface receptors and prevent activation of TGF-ß signaling. We have demonstrated that the loss of TßRIII shedding, generated through a single base pair mutation in TßRIII (M740A), increases TGF-ß signaling, and inhibits tumorigenicity and metastasis in vivo. However, the mechanism of TßRIII shedding and the relative contributions of sTßRIII versus cell-surface TßRIII to cancer initiation and progression have not been investigated and remain a fundamental barrier to developing novel therapeutic agents that target sTßRIII/TßRIII and TGF-ß superfamily signaling pathways. Protease predictions from PROSPER and preliminary data using TAPI-2, a broad spectrum inhibitor of members of the matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM) families, suggest that TßRIII shedding is mediated by proteases in the MMP or ADAM family. This project will seek to identify the proteases involved in TßRIII shedding using a combination of loss (shRNA, inhibitors) and gain of function (expression, recombinant protein) approaches. We will also investigate the biological contributions of soluble and cell- surface TßRIII to anchorage-independent cell growth, migration, invasion, proliferation, and TGF-ß signaling in lung adenocarcinoma cell lines that are deficient in TßRIII cleavage. To study the in vivo contributions of sTßRIII to cancer initiation and progression, we are developing an in vivo TßRIIIM70A/M740A;FSF-KrasG12D/+ lung carcinoma model in which there is a loss of sTßRIII production. We anticipate that loss of TßRIII shedding will delay tumorigenesis while promoting tumor growth and metastasis after tumor initiation due to the dual effects of TGF-ß as a tumor suppressor early in carcinogenesis and then later, as a tumor promoter. This work will define the roles of cell surface and sTßRIII in carcinogenesis by providing a mechanistic understanding of the protease(s) involved in the generation of sTßRIII and the contributions of sTßRIII to lung adenocarcinoma development and progression, which may lead to the development of new therapeutic strategies that target TßRIII shedding or TGFß superfamily signaling pathways.

 描述（由申请人提供）：转化生长因子-β（TGF-β）参与癌症生物学的许多方面，包括增殖、凋亡、迁移和转移. TGF-β的作用通过细胞表面受体家族介导，包括III型TGF-β受体（T β RIII），其可介导下游信号传导。T β RIII在包括非小细胞肺癌（NSCLC）在内的许多人类癌症中丢失，丢失与更具侵袭性的疾病和疾病进展相关。T β RIII还经历胞外域切割，产生可溶性蛋白质（sT β RIII），其可将配体与细胞表面受体隔离并防止TGF-β信号传导的活化。我们已经证明，通过T β RIII（M740 A）中的单碱基对突变产生的T β RIII脱落的丧失增加了TGF-β信号传导，并抑制了体内致瘤性和转移。然而，T β RIII脱落的机制以及sT β RIII与细胞表面T β RIII对癌症发生和进展的相对贡献尚未得到研究，并且仍然是开发靶向sT β RIII/T β RIII和TGF-β超家族信号传导途径的新型治疗药物的根本障碍。来自PROSPER的蛋白酶预测和使用TAPI-2（基质金属蛋白酶（MMP）和去整合素和金属蛋白酶（ADAM）家族成员的广谱抑制剂）的初步数据表明，T β RIII脱落由MMP或ADAM家族中的蛋白酶介导。该项目将寻求使用功能丧失（shRNA，抑制剂）和功能获得（表达，重组蛋白）方法的组合来鉴定参与TßRIII脱落的蛋白酶。我们还将研究可溶性和细胞表面T β RIII对锚定非依赖性细胞生长、迁移、侵袭、增殖的生物学贡献， 和TGF-β 1信号传导在缺乏T β RIII切割的肺腺癌细胞系中的作用。为了研究sT β RIII对癌症发生和发展的体内作用，我们正在开发 体内T β RIIIM 70 A/M740 A; FSF-KrasG 12 D/+肺癌模型，其中sT β RIII产生丧失。我们预期，由于TGF-β 1在癌发生早期作为肿瘤抑制剂，然后在晚期作为肿瘤促进剂的双重作用，T3 RIII脱落的丧失将延迟肿瘤发生，同时在肿瘤起始后促进肿瘤生长和转移。这项工作将通过提供对参与sT β RIII生成的蛋白酶的机制理解以及sT β RIII对肺腺癌发展和进展的贡献来定义细胞表面和sT β RIII在致癌作用中的作用，这可能导致靶向T β RIII脱落或TGF β超家族信号通路的新治疗策略的开发。