Mesenchymal stromal cells (MSCs) are key contributors of the tumour microenvironment and are known to promote cancer progression through reciprocal communication with cancer cells, but how they become activated is not fully understood. Here, we investigate how breast cancer cells from different stages of the metastatic cascade convert MSCs into tumour-associated MSCs (TA-MSCs) using unbiased, global approaches. Using mass spectrometry, we compared the secretomes of MCF-7 cells, invasive MDA-MB-231 cells, and sublines isolated from bone, lung, and brain metastases and identified ECM and exosome components associated with invasion and organ-specific metastasis. Next, we used synthetic hydrogels to investigate how these different secretomes activate MSCs in bioengineered 3D microenvironments. Using kinase activity profiling and RNA sequencing, we found that only MDA-MB-231 breast cancer secretomes convert MSCs into TA-MSCs, resulting in an immunomodulatory phenotype that was particularly prominent in response to bone-tropic cancer cells. We have investigated paracrine signalling from breast cancer cells to TA-MSCs in 3D, which may highlight new potential targets for anticancer therapy approaches aimed at targeting tumour stroma.

中文翻译：

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在生物工程3D微环境中，乳腺癌的分泌组激活间充质基质细胞。

间充质基质细胞（MSCs）是肿瘤微环境的关键因素，并且已知通过与癌细胞的相互通讯来促进癌症的进展，但是它们如何被激活尚不完全清楚。在这里，我们研究了如何利用无偏见，全局性方法将转移级联反应不同阶段的乳腺癌细胞转化为肿瘤相关的MSC（TA-MSC）。使用质谱法，我们比较了MCF-7细胞，侵袭性MDA-MB-231细胞以及从骨，肺和脑转移物中分离的亚系的分泌组，并鉴定了与侵袭和器官特异性转移相关的ECM和外泌体成分。接下来，我们使用合成水凝胶来研究这些不同的分泌组如何激活生物工程3D微环境中的MSC。使用激酶活性分析和RNA测序，我们发现只有MDA-MB-231乳腺癌分泌基因组将MSC转化为TA-MSC，从而导致免疫调节表型在对骨癌细胞的应答中尤为突出。我们已经研究了从乳腺癌细胞到TA-MSCs的旁分泌信号传导3D模式，这可能突出了针对肿瘤基质的抗癌治疗方法的新潜在靶点。