Integrative Oncology, BC Cancer, Vancouver, British Columbia, BC V5Z 4E6, Canada.
Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, British Columbia, BC V5Z 4H4, Canada.
Mol Biol Cell. 2021 Apr 1;32(7):567-578. doi: 10.1091/mbc.E20-01-0060. Epub 2021 Feb 10.
The ability of cancer cells to invade surrounding tissues requires degradation of the extracellular matrix (ECM). Invasive structures, such as invadopodia, form on the plasma membranes of cancer cells and secrete ECM-degrading proteases that play crucial roles in cancer cell invasion. We have previously shown that the protein tyrosine phosphatase alpha (PTPα) regulates focal adhesion formation and migration of normal cells. Here we report a novel role for PTPα in promoting triple-negative breast cancer cell invasion in vitro and in vivo. We show that PTPα knockdown reduces ECM degradation and cellular invasion of MDA-MB-231 cells through Matrigel. PTPα is not a component of TKS5-positive structures resembling invadopodia; rather, PTPα localizes with endosomal structures positive for MMP14, caveolin-1, and early endosome antigen 1. Furthermore, PTPα regulates MMP14 localization to plasma membrane protrusions, suggesting a role for PTPα in intracellular trafficking of MMP14. Importantly, we show that orthotopic MDA-MB-231 tumors depleted in PTPα exhibit reduced invasion into the surrounding mammary fat pad. These findings suggest a novel role for PTPα in regulating the invasion of triple-negative breast cancer cells.
癌细胞侵袭周围组织的能力需要降解细胞外基质（ECM）。侵袭结构，如侵袭伪足，在癌细胞的质膜上形成，并分泌 ECM 降解蛋白酶，在癌细胞侵袭中发挥关键作用。我们之前已经表明，蛋白酪氨酸磷酸酶α（PTPα）调节正常细胞的粘着斑形成和迁移。在这里，我们报告了 PTPα 在促进体外和体内三阴性乳腺癌细胞侵袭中的新作用。我们发现 PTPα 敲低通过 Matrigel 减少了 MDA-MB-231 细胞的 ECM 降解和细胞侵袭。PTPα 不是类似于侵袭伪足的 TKS5 阳性结构的组成部分；相反，PTPα 与 MMP14、 caveolin-1 和早期内体抗原 1 阳性的内体结构定位。此外，PTPα 调节 MMP14 向质膜突起的定位，表明 PTPα 在 MMP14 的细胞内运输中起作用。重要的是，我们发现 PTPα 耗尽的 MDA-MB-231 原位肿瘤在周围乳腺脂肪垫中的侵袭性降低。这些发现表明 PTPα 在调节三阴性乳腺癌细胞侵袭中的新作用。
