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

Duke University, Durham NC

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Abstract

? 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.