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.
|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|
|Gilbert, Penney M; Weaver, Valerie M (2016) Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease. Semin Cell Dev Biol :|
|Kaushik, Shelly; Pickup, Michael W; Weaver, Valerie M (2016) From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev :|
|Lehmann, Brian D; JovanoviÄ‡, Bojana; Chen, Xi et al. (2016) Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One 11:e0157368|
|Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-97|
|Northcott, Josette M; Northey, Jason J; Barnes, J Matthew et al. (2015) Fighting the force: Potential of homeobox genes for tumor microenvironment regulation. Biochim Biophys Acta 1855:248-53|
|Acerbi, I; Cassereau, L; Dean, I et al. (2015) Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb) 7:1120-34|
|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) TGFÎ² signaling in myeloid cells regulates mammary carcinoma cell invasion through fibroblast interactions. PLoS One 10:e0117908|
|Cassereau, Luke; Miroshnikova, Yekaterina A; Ou, Guanqing et al. (2015) A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype. J Biotechnol 193:66-9|
Showing the most recent 10 out of 69 publications