Tumor heterogeneity, the presence of multiple distinct subpopulations of cancer cells between patients or among the same tumors, poses a major challenge to current targeted therapies. The way these different subpopulations interact among themselves and the stromal niche environment, and how such interactions affect cancer stem cell behavior has remained largely unknown. Here, it is shown that an FGF‐BMP7‐INHBA signaling positive feedback loop integrates interactions among different cell populations, including mammary gland stem cells, luminal epithelial and stromal fibroblast niche components not only in organ regeneration but also, with certain modifications, in cancer progression. The reciprocal dependence of basal stem cells and luminal epithelium is based on basal‐derived BMP7 and luminal‐derived INHBA, which promote their respective expansion, and is regulated by stromal‐epithelial FGF signaling. Targeting this interaction loop, for example, by reducing the function of one or more of its components, inhibits organ regeneration and breast cancer progression. The results have profound implications for overcoming drug resistance because of tumor heterogeneity in future targeted therapies.

中文翻译：

---

通过打破干细胞和上皮微环境相互作用环来靶向肿瘤异质性

肿瘤异质性，即患者之间或同一肿瘤之间存在多个不同的癌细胞亚群，对当前的靶向治疗提出了重大挑战。这些不同的亚群之间以及基质生态位环境之间相互作用的方式，以及这种相互作用如何影响癌症干细胞的行为仍然很大程度上未知。在这里，研究表明，FGF-BMP7-INHBA 信号正反馈环路整合了不同细胞群之间的相互作用，包括乳腺干细胞、管腔上皮和基质成纤维细胞生态位成分，不仅在器官再生中，而且经过某些修改，在癌症中进展。基底干细胞和管腔上皮的相互依赖性基于基底衍生的 BMP7 和管腔衍生的 INHBA，促进它们各自的扩张，并受到基质上皮 FGF 信号传导的调节。例如，通过降低其一种或多种成分的功能来靶向这种相互作用循环，从而抑制器官再生和乳腺癌进展。由于未来靶向治疗中肿瘤异质性，这些结果对于克服耐药性具有深远的意义。