Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Department of Pathology, The International Peace Maternity and Child Health Hospital of China Welfare Institution, School of Medicine, Shanghai Jiao Tong University, 910 Hengshan Road, Shanghai, 200030, People's Republic of China.
Breast Cancer Res. 2023 Jul 28;25(1):90. doi: 10.1186/s13058-023-01683-8.
The communication between tumor cells and tumor microenvironment plays a critical role in cancer development. Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and take part in breast cancer formation and progression. Here, by comparing the gene expression patterns in CAFs and normal fibroblasts, we found SPRY2 expression was significantly decreased in CAFs and decreased SPRY2 expression was correlated with worse prognosis in breast cancer patients. SPRY2 knockdown in fibroblasts promoted tumor growth and distant metastasis of breast cancer in mice. Loss of stromal SPRY2 expression promoted CAF activation dependent on glycolytic metabolism. Mechanically, SPRY2 suppressed Y10 phosphorylation of LDHA and LDHA activity by interfering with the interaction between LDHA and SRC. Functionally, SPRY2 knockdown in fibroblasts enhanced the stemness of tumor cell dependent on glycolysis in fibroblasts. Collectively, this work identified SPRY2 as a negative regulator of CAF activation, and SPRY2 in CAFs may potentially be therapeutically targeted in breast cancer treatment.
肿瘤细胞与肿瘤微环境之间的通讯在癌症发展中起着关键作用。癌症相关成纤维细胞（CAFs）是肿瘤微环境的主要组成部分，并参与乳腺癌的形成和发展。在这里，通过比较 CAFs 和正常成纤维细胞中的基因表达模式，我们发现 CAFs 中的 SPRY2 表达显著降低，且 SPRY2 表达降低与乳腺癌患者的预后不良相关。成纤维细胞中的 SPRY2 敲低促进了乳腺癌在小鼠中的肿瘤生长和远处转移。基质 SPRY2 的缺失促进了 CAF 的激活，依赖于糖酵解代谢。在机制上，SPRY2 通过干扰 LDHA 和 SRC 之间的相互作用抑制了 LDHA 的 Y10 磷酸化和 LDHA 活性。在功能上，成纤维细胞中的 SPRY2 敲低增强了依赖于成纤维细胞糖酵解的肿瘤细胞的干性。总的来说，这项工作确定了 SPRY2 是 CAF 激活的负调节剂，CAFs 中的 SPRY2 可能成为乳腺癌治疗中潜在的治疗靶点。
