The TGF-? pathway potently regulates tumor initiation, progression and metastasis. Work supported by this grant over the current funding period has shown that impairment of TGF-? signaling, when combined with oncogene activation or tumor suppressor gene attenuation, accelerates the development of carcinomas and enhances tumor progression, including metastasis. Mechanistic studies utilizing the mammary gland models, MMTV-PyMT and MMTV- c-neu, have shown that a major mechanism whereby loss or attenuation of TGF-? signaling accelerates tumor progression is increased secretion of cytokines and chemokines by . In the mouse models increased chemokine expression resulted in recruitment of myeloid/immune cells with resultant enhancement of invasion and metastasis. We now have another model in which a single genetic alteration results in a 4-5 fold increase in lung metastases with different mechanisms. The following three hypotheses will be tested in the proposed studies: 1) A major function of TGF-? signaling is the suppression of chemokine and cytokine expression, and attenuation or loss of TGF-? signaling in carcinoma cells leads to increased secretion of different chemokines and cytokines that play different roles in enhancing metastasis. 2) A mechanism of myeloid/immune cell enhancement of tumor invasion and metastasis is through secretion of TGF-?, which induces lysyl oxidase (LOX) that cross-links collagen increasing matrix stiffness and enhancing invasion. 3) The gene expression signature and patterns of expression of selected chemokines and cytokines in tissue microarrays (TMA) of impaired TGF-? signaling in our models will predict for worse outcome when applied to publically available human breast cancer datasets. The following specific aims are proposed to test these hypotheses: 1) Determine the mechanism of enhancement of c-neu-induced tumor metastasis by a dominant negative type II TGF-? receptor (DNIIR);2) determine the mechanism(s) of myeloid/immune cell promotion of tumor invasion and metastasis in the PyMT model with conditional knockout of the type II TGF-? receptor and in the c-neu/DNIIR model;and 3) Determine whether mechanisms identified in the mouse models are applicable to human breast cancer.
TGF- signaling is a major tumor suppressor pathway in human carcinomas; but in later stages of tumor progression; TGF- signaling promotes tumor progression. As systemic inhibitors of TGF- signaling are in clinical trials in humans with cancer; it is important to delineate mechanisms of both suppression and promotion of tumors by TGF- . We have excellent mouse models and plans for such mechanistic studies.
|Tharp, Kevin M; Weaver, Valerie M (2018) Modeling Tissue Polarity in Context. J Mol Biol 430:3613-3628|
|Gilbert, Penney M; Weaver, Valerie M (2017) Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease. Semin Cell Dev Biol 67:141-152|
|Lehmann, Brian D; Jovanovi?, Bojana; Chen, Xi et al. (2016) Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One 11:e0157368|
|Ou, Guanqing; Thakar, Dhruv; Tung, Jason C et al. (2016) Visualizing mechanical modulation of nanoscale organization of cell-matrix adhesions. Integr Biol (Camb) 8:795-804|
|Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-497|
|Kaushik, Shelly; Pickup, Michael W; Weaver, Valerie M (2016) From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev 35:655-667|
|Oudin, Madeleine J; Weaver, Valerie M (2016) Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis. Cold Spring Harb Symp Quant Biol 81:189-205|
|Hover, Laura D; Abel, Ty W; Owens, Philip (2015) Genomic Analysis of the BMP Family in Glioblastomas. Transl Oncogenomics 7:1-9|
|Shaw, Aubie K; Pickup, Michael W; Chytil, Anna et al. (2015) TGF? signaling in myeloid cells regulates mammary carcinoma cell invasion through fibroblast interactions. PLoS One 10:e0117908|
|Hover, Laura D; Young, Christian D; Bhola, Neil E et al. (2015) Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth. Cancer Lett 368:79-87|
Showing the most recent 10 out of 70 publications