It is now widely accepted that the TGF-B signaling pathways can both suppress tumor formation and promote tumor progression and that both effects are mediated largely through tumor cell autonomous TGF-B signaling. Data generated during this grant period with conditional knockout of TGF-B signaling in epithelia support the hypothesis that epithelial cell autonomous TGF-15 signaling is tumor suppressive and demonstrate that metastases can not only occur but are enhanced with knockout of the type II TGF-B receptor (Tgfbr2) in mammary carcinoma cells. However, systemic inhibition of TGF-IS signaling markedly suppressed pulmonary metastases in the MMTV-c-neu/DNIIR mice. This indicates that the effect of systemic inhibitors of TGF-IS in suppressing metastasis is largely on host cells. These results have modified our hypotheses concerning the mechanism of TGF-B promotion of tumor progression. We now propose that tumor cell autonomous signaling by TGF-li can suppress rather than enhancing metastases, and that TGF-B signaling in host cells is a significant component of both the tumor suppressive and the tumor promotion effects of TGF-fi in vivo. We will test these hypotheses through the following specific aims by determining the changes in the carcinoma cells and their microenvironment associated with knockout of the type II TGF-li receptor gene, Tgfbr2, in tumor cells that lead to increased metastases.
Specific Aim 1. Determine the effects of systemic inhibition of TGF-IS signaling on mammary tumor formation and metastases from MMTV- c-neu and MMTV-PyVmT-induced mammary tumors in the context Tgfbr2 knockout in mammary epithelial cells effected by both MMTV-Cre and WAP-Cre.
Specific Aim 2. Determine the influence of timing of loss of TGF-B signaling during mammary tumor formation and progression on metastatic spread using inducible MMTV-Cre.
Specific Aim 3. Determine mechanisms for enhanced metastatic capability with loss of tumor cell TGF-li signaling by examining both tumor cells and their microenvironment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
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 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
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
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; Abel, Ty W; Owens, Philip (2015) Genomic Analysis of the BMP Family in Glioblastomas. Transl Oncogenomics 7:1-9
Pickup, Michael W; Hover, Laura D; Polikowsky, Eleanor R et al. (2015) BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation. Mol Oncol 9:179-91
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 69 publications