A major challenge to the prevention or treatment of breast cancer metastasis is to understand how tumors respond to environmental signals that regulate their invasive/migratory capacity and then develop selective therapeutic strategies to abrogate these processes. We have identified a novel pathway (the cell surface receptor tyrosine kinase discoidin domain receptor 2 (DDR2)) turned on in breast cancer cells and activated by tumor environmental signals (fibrillar collagen) that is critical for breast cancer metastasis. DDR2 is present on 70% of human invasive breast tumor cells including all clinical subtypes and also invasive DCIS. Importantly DDR2 is not expressed by normal breast epithelia. We have now identified a group of potent and selective novel small molecules that interact with the extracellular domain (ECD) of DDR2 to inhibit DDR2 binding to, and activation by collagen I. When invasive human breast cancer cell lines that express DDR2 are treated with these molecules the activation of DDR2, cell proliferation, and tumor cell invasion are inhibited. We hypothesize that the RTK, DDR2, is a new target for the treatment of breast cancer metastasis and that novel inhibitors targeting the ECD of DDR2 to prevent its activation will be effective in the prevention and, or treatment of breast cancer metastasis. To test these two hypothesis we shall first determine which DDR2 expressing cells within the tumor (epithelial and, or stroma) are critical for DDR2's action in the regulation of breast cancer metastasis and how. Then determine how our novel small molecules inhibit cellular signaling and cellular functions mediated by DDR2 in tumor cells and cancer associated fibroblasts (CAFs), and whether these molecules synergizes with TK inhibitors of DDR2 (Aim 2). Determine the molecular basis for inhibition of DDR2 activation by these novel molecules by solving the crystal structure of the ECD of DDR2 in a complex with inhibitor and ligand (Aim 3). Finally in Aim 4 we will determine if these novel inhibitors of DDR2 block breast cancer metastasis development and regression of already established metastases in vivo.
The majority of breast cancer deaths result from metastatic disease; basic research into understanding the biology underlying progression of breast cancer has helped identify promising molecular targets to prevent or inhibit breast cancer metastasis. Recent work has identified changes within the tumor microenvironment as being critical for tumor progression and response to therapies. During tumor progression the structure of the tumor stromal is remodeled and these changes facilitate tumor cell invasion yet how is not fully understood but clearly important to determine if we are to therapeutically intervene.
|Grither, Whitney R; Divine, Laura M; Meller, Eric H et al. (2018) TWIST1 induces expression of discoidin domain receptor 2 to promote ovarian cancer metastasis. Oncogene 37:1714-1729|
|Brenot, Audrey; Knolhoff, Brett L; DeNardo, David G et al. (2018) SNAIL1 action in tumor cells influences macrophage polarization and metastasis in breast cancer through altered GM-CSF secretion. Oncogenesis 7:32|
|Grither, Whitney R; Longmore, Gregory D (2018) Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain. Proc Natl Acad Sci U S A 115:E7786-E7794|
|Sewell-Loftin, Mary Kathryn; Bayer, Samantha Van Hove; Crist, Elizabeth et al. (2017) Cancer-associated fibroblasts support vascular growth through mechanical force. Sci Rep 7:12574|
|Nasrollahi, Samila; Walter, Christopher; Loza, Andrew J et al. (2017) Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory. Biomaterials 146:146-155|
|Ye, Xin; Brabletz, Thomas; Kang, Yibin et al. (2017) Upholding a role for EMT in breast cancer metastasis. Nature 547:E1-E3|
|Biswas, Hirak; Longmore, Gregory D (2016) Action of SNAIL1 in Cardiac Myofibroblasts Is Important for Cardiac Fibrosis following Hypoxic Injury. PLoS One 11:e0162636|
|Loza, Andrew J; Koride, Sarita; Schimizzi, Gregory V et al. (2016) Cell density and actomyosin contractility control the organization of migrating collectives within an epithelium. Mol Biol Cell 27:3459-3470|
|Corsa, Callie A S; Brenot, Audrey; Grither, Whitney R et al. (2016) The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer Metastasis. Cell Rep 15:2510-23|
|Jagannathan, Radhika; Schimizzi, Gregory V; Zhang, Kun et al. (2016) AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol. Mol Cell Biol 36:2526-42|
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