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

项目摘要 每年约有45万妇女死于乳腺癌，使其成为最常见的癌症。 癌症是全球女性癌症死亡的主要原因，其中大多数死亡是由转移性疾病引起的。 在转移瘤的治疗中，初始药物反应率仅为约50%，而观察到的反应率为90 原发性肿瘤的治疗。此外，对这些全身治疗的耐药性通常会发展为 在转移性疾病中会更快。虽然许多研究都集中在肿瘤细胞内在 转移和耐药性的机制，很少有研究如何非- 转移性肿瘤微环境的恶性宿主细胞额外地促进这些过程。 成纤维细胞是肿瘤微环境中存在的一种细胞类型，与多种肿瘤有关 生长和转移促进活性。尽管有这种新兴的模式，很少有研究评估 肺成纤维细胞对癌细胞存活和化疗耐药的外在机制的贡献， 这反映了在体内进行这些研究的困难，以及缺乏体外模型， 可靠地再现体内肿瘤-基质相互作用。我们的实验室已经完全优化了一个3D肺样 有效地合并肿瘤细胞和原代驻留基质细胞的器官型共培养模型 转移的继发部位。利用这个模型，我们的初步数据表明，肺成纤维细胞， 调节人乳腺癌细胞增殖和药物反应的显著表型差异， 乳腺癌的分子亚型依赖方式。基于这些数据，我们假设我们可以 鉴定肿瘤细胞特异性基因，其功能对于它们获得促存活和药物治疗是必需 耐药表型与肺成纤维细胞相互作用。为了调查这一点，我们建议进行一次 全基因组CRISPR“基质合成致死”筛选培养在 存在或不存在原代人肺成纤维细胞。这些研究的结果将填补关键的知识 关于肺成纤维细胞介导的促进乳腺癌生存的空白，并将发现新的基因 其功能/蛋白质可作为乳腺癌潜在的新型抗转移疗法进行靶向评估 癌

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.