Bulk and single cell transcriptomic profiling of breast cancer cell - lung fibroblast co-cultures

The tumor microenvironment (TME) can regulate breast cancer cell behavior therapy responses in primary breast tumors, but composition and contributions of the metastatic TME to therapy resistance remain poorly understood, especially in lung-metastatic breast cancer. Here, we demonstrate the utility of a breast cancer cell - primary lung fibroblast co-culture for uncovering mechanisms of stromal-mediated resistance in breast cancer cells and screening for therapeutic vulnerabilities unique to this setting. Using this model in drug screening, transcriptomic analyses, and in vitro functional assays, we describe a novel mechanism of extrinsic, lung stroma-mediated resistance where cell juxtacrine signaling from lung fibroblasts induces a dormant-like, therapy resistant state in breast cancer cells associated with Janus-family kinase-dependent upregulation of macroautophagy.

肿瘤微环境（tumor microenvironment, TME）可调控原发性乳腺肿瘤内乳腺癌细胞的行为与治疗应答，但转移性肿瘤微环境的组成及其对治疗耐药性的贡献仍未得到充分阐明，尤其在肺转移性乳腺癌中。本研究证实了乳腺癌细胞与原代肺成纤维细胞共培养模型的应用价值，该模型可用于解析乳腺癌细胞的基质介导耐药机制，并筛选该特定微环境下独有的治疗易感靶点。通过该模型开展药物筛选、转录组学分析及体外功能实验，本研究揭示了一种全新的肺基质介导的外源性耐药机制：肺成纤维细胞通过邻分泌信号（juxtacrine signaling）诱导乳腺癌细胞进入休眠样治疗耐药状态，该过程与贾纳斯家族激酶（Janus-family kinase）依赖的巨自噬（macroautophagy）上调密切相关。