Elucidating the role and regulation of periostin in therapy-induced chemoresistance in metastatic breast cancer

项目总结

Project Summary Approximately 450,000 women succumb to breast cancer each year, making it the most common cause of female cancer mortality globally, with the majority of these deaths resulting from metastatic disease. In the treatment of metastases, the initial drug response rate is only about 50%, as compared to 90% observed in the treatment of primary tumors. Furthermore, resistance to these systemic therapies typically develops more quickly in the metastatic setting. While numerous studies have focused on tumor cell intrinsic mechanisms of metastasis and drug resistance, there have been very few investigations into how non- malignant host cells of the metastatic tumor microenvironment extrinsically promote these processes. Fibroblasts are one cell type present in the tumor microenvironment which have been linked to several tumor growth and metastasis promoting activities. Despite this emerging paradigm, very few studies have evaluated the contributions of lung fibroblasts to extrinsic mechanisms of cancer cell survival and chemo-resistance, a reflection of the difficulty of conducting these investigations in vivo, and the paucity of in vitro models which reliably recapitulate in vivo tumor-stroma interactions. Our laboratory has fully optimized a 3D lung-like organotypic co-culture model which effectively incorporates both tumor cells and primary resident stromal cells from secondary sites of metastasis. Utilizing this model, our preliminary data demonstrate that lung fibroblasts modulate significant phenotypic differences in human breast cancer cell proliferation and drug response, in a breast cancer molecular-subtype dependent manner. Based on these data, we hypothesize that we can identify tumor cell specific genes whose function is essential for their attainment of pro-survival and drug resistant phenotypes upon interaction with lung fibroblasts. To investigate this, we propose to conduct a genome-wide CRISPR “stromal synthetic lethal” screen against human breast cancer cells cultured in the presence or absence of primary human lung fibroblasts. Results of these studies will fill a critical knowledge gap regarding lung fibroblast mediated promotion of breast cancer survival and will uncover novel genes whose function/proteins can be targeted for assessment as potential novel anti-metastatic therapies for breast cancer.