Trepicchio Colin, Rauner Gat, Traugh Nicole, Wang Ruohong, Parrish Meadow, Fein Daniel E C, Mal Youssof, Gupta Piyush B, Monti Stefano, Kuperwasser Charlotte
Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
Bioinformatics Program, Faculty of Computing & Data Science, Boston University, Boston, MA 02215, USA.
Stem Cell Reports. 2025 Aug 12;20(8):102576. doi: 10.1016/j.stemcr.2025.102576. Epub 2025 Jul 3.
Understanding epithelial stem cell differentiation and morphogenesis during breast tissue development is essential, as disruption in these processes underlie breast cancer formation. We used a next-generation single-cell-derived organoid model to investigate how individual stem cells give rise to complex tissue. We show that discoidin domain receptor 1 (DDR1) inhibition traps cells in a bipotent state, blocking alveolar morphogenesis and luminal cell expansion, which is necessary for complex epithelium formation. Disrupting RUNX1 function produced nearly identical phenotypes, underscoring its critical role downstream of DDR1. Mechanistically, DDR1 affects the interaction and expression of RUNX1 and its cofactor core binding factor beta (CBFβ), thereby regulating its activity. Mutational analyses in breast cancer patients reveal frequent alterations in the DDR1-RUNX1 signaling axis, particularly co-occurring mutations. Together, these findings uncover DDR1-RUNX1 as a central signaling pathway driving breast epithelial differentiation, whose dysregulation may contribute fundamentally to breast cancer pathogenesis.
了解乳腺组织发育过程中的上皮干细胞分化和形态发生至关重要，因为这些过程的破坏是乳腺癌形成的基础。我们使用了一种新一代单细胞衍生类器官模型来研究单个干细胞如何形成复杂组织。我们发现，盘状结构域受体1（DDR1）的抑制作用会使细胞陷入双能状态，阻止肺泡形态发生和管腔细胞扩张，而这是形成复杂上皮所必需的。破坏RUNX1功能会产生几乎相同的表型，突显了其在DDR1下游的关键作用。从机制上讲，DDR1影响RUNX1及其辅因子核心结合因子β（CBFβ）的相互作用和表达，从而调节其活性。对乳腺癌患者的突变分析揭示了DDR1-RUNX1信号轴的频繁改变，特别是同时发生的突变。这些发现共同揭示了DDR1-RUNX1是驱动乳腺上皮分化的核心信号通路，其失调可能从根本上导致乳腺癌的发病机制。
