Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.
Department of Biotechnology, Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey.
Autophagy. 2023 Jan;19(1):306-323. doi: 10.1080/15548627.2022.2090693. Epub 2022 Jun 28.
Macroautophagy/autophagy is an evolutionarily conserved cellular stress response mechanism. Autophagy induction in the tumor microenvironment (stroma) has been shown to support tumor metabolism. However, cancer cell-derived secreted factors that initiate communication with surrounding cells and stimulate autophagy in the tumor microenvironment are not fully documented. We identified CTF1/CT-1 (cardiotrophin 1) as an activator of autophagy in fibroblasts and breast cancer-derived carcinoma-associated fibroblasts (CAFs). We showed that CTF1 stimulated phosphorylation and nuclear translocation of STAT3, initiating transcriptional activation of key autophagy proteins. Additionally, following CTF1 treatment, AMPK and ULK1 activation was observed. We provided evidence that autophagy was important for CTF1-dependent ACTA2/α-SMA accumulation, stress fiber formation and fibroblast activation. Moreover, promotion of breast cancer cell migration and invasion by activated fibroblasts depended on CTF1 and autophagy. Analysis of the expression levels of CTF1 in patient-derived breast cancer samples led us to establish a correlation between CTF1 expression and autophagy in the tumor stroma. In line with our data on cancer migration and invasion, higher levels of CTF1 expression in breast tumors was significantly associated with lymph node metastasis in patients. Therefore, CTF1 is an important mediator of tumor-stroma interactions, fibroblast activation and cancer metastasis, and autophagy plays a key role in all these cancer-related events. ACTA2/α-SMA: actin, alpha 2, smooth muscle CAFs: cancer- or carcinoma-associated fibroblasts CNT Ab.: control antibody CNTF: ciliary neurotrophic factor CTF1: cardiotrophin 1 CTF1 Neut. Ab.: CTF1-specific neutralizing antibody GFP-LC3 MEF: GFP-fused to MAP1LC3 protein transgenic MEF LIF: leukemia inhibitory factor IL6: interleukin 6 MEFs: mouse embryonic fibroblasts MEF-WT: wild-type MEFs OSM: oncostatin M TGFB/TGFβ: transforming growth factor beta.
自噬是一种进化上保守的细胞应激反应机制。已经表明，肿瘤微环境（基质）中的自噬诱导支持肿瘤代谢。然而，启动与周围细胞的通信并刺激肿瘤微环境中自噬的癌细胞衍生的分泌因子尚未得到充分记录。我们鉴定出 CTF1/CT-1（心肌营养素 1）是成纤维细胞和乳腺癌衍生的癌相关成纤维细胞（CAFs）中自噬的激活剂。我们表明，CTF1 刺激 STAT3 的磷酸化和核易位，启动关键自噬蛋白的转录激活。此外，在用 CTF1 处理后，观察到 AMPK 和 ULK1 的激活。我们提供的证据表明，自噬对于 CTF1 依赖性 ACTA2/α-SMA 积累、应激纤维形成和成纤维细胞激活很重要。此外，激活的成纤维细胞促进乳腺癌细胞迁移和侵袭取决于 CTF1 和自噬。对患者来源的乳腺癌样本中 CTF1 表达水平的分析使我们建立了肿瘤基质中 CTF1 表达与自噬之间的相关性。与我们关于癌症迁移和侵袭的数据一致，乳腺癌肿瘤中 CTF1 表达水平较高与患者的淋巴结转移显著相关。因此，CTF1 是肿瘤-基质相互作用、成纤维细胞激活和癌症转移的重要介质，自噬在所有这些与癌症相关的事件中都发挥关键作用。ACTA2/α-SMA：肌动蛋白，α2，平滑肌 CAFs：癌或癌相关成纤维细胞 CNT Ab.：对照抗体 CNTF：睫状神经营养因子 CTF1：心肌营养素 1 CTF1 Neut. Ab.：CTF1 特异性中和抗体 GFP-LC3 MEF：GFP 融合到 MAP1LC3 蛋白的转基因 MEF LIF：白血病抑制因子 IL6：白细胞介素 6 MEFs：小鼠胚胎成纤维细胞 MEF-WT：野生型 MEFs OSM：肿瘤坏死因子 M TGFB/TGFβ：转化生长因子 β。
