The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.

肿瘤微环境（TME）是乳腺癌进展的重要介质。癌症相关成纤维细胞构成 TME 的主要成分，可能源自组织相关成纤维细胞或浸润性间充质基质细胞 (MSC)。癌细胞激活成纤维细胞并将 MSC 募集到 TME 的机制在很大程度上是未知的，但可能包括促肿瘤分泌组的沉积。分泌的胚胎蛋白 NODAL 在临床上与乳腺癌分期相关，并促进肿瘤生长、转移和血管形成。在此，我们表明 NODAL 表达与人类三阴性乳腺癌中活化成纤维细胞的存在相关，并且它直接诱导癌症相关成纤维细胞表型。我们进一步表明，NODAL 通过同时改变趋化因子（例如，CXCL1）、细胞因子（例如，IL-6）和生长因子（例如，PDGFRA）的水平来重新编程癌细胞分泌组，从而导致 MSC 趋化性的改变。因此，我们展示了 TME 动态调节的一种迄今为止未被重视的机制。