Corsa Callie A S, Brenot Audrey, Grither Whitney R, Van Hove Samantha, Loza Andrew J, Zhang Kun, Ponik Suzanne M, Liu Yuming, DeNardo David G, Eliceiri Kevin W, Keely Patricia J, Longmore Gregory D
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Cell Rep. 2016 Jun 14;15(11):2510-23. doi: 10.1016/j.celrep.2016.05.033. Epub 2016 Jun 2.
High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.
由于局部侵袭增加和远处转移，人类和小鼠乳腺肿瘤中高水平的胶原蛋白沉积与不良预后相关。通过遗传学方法，我们发现，在小鼠中，纤维状胶原蛋白受体盘状结构域受体2（DDR2）在肿瘤细胞和肿瘤基质细胞中的作用对于乳腺癌转移至关重要，但不影响原发性肿瘤生长。在肿瘤细胞中，基底上皮细胞中的DDR2调节肿瘤类器官的集体侵袭。在基质癌相关成纤维细胞（CAF）中，DDR2对于细胞外基质的产生和胶原纤维的组织至关重要。DDR2在CAF中的作用还通过一条不同于DDR2肿瘤细胞内在功能的途径增强肿瘤细胞的集体侵袭。这项研究将DDR2确定为一个潜在的治疗靶点，它通过在原发性肿瘤部位的肿瘤细胞和肿瘤基质细胞中的作用来控制乳腺癌转移。
