Tumor-derived CTF1 (cardiotrophin 1) is a critical mediator of stroma-assisted and autophagy-dependent breast cancer cell migration, invasion and metastasis

Akkoç, Yunus and Dalci, Kubilay and Karakaş Schüller, Hacer Ezgi and Erbil Bilir, Seçil and Yalav, Orcun and Sakman, Gurhan and Celik, Faruk and Arikan, Soykan and Zeybek, Umit and Ergin, Melek and Akkiz, Hikmet and Dilege, Ece and Dengjel, Joern and Dogan-Ekici, A. Isin and Gözüaçık, Devrim (2023) Tumor-derived CTF1 (cardiotrophin 1) is a critical mediator of stroma-assisted and autophagy-dependent breast cancer cell migration, invasion and metastasis. Autophagy, 19 (1). pp. 306-323. ISSN 1554-8627 (Print) 1554-8635 (Online)

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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/alpha-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 in vitro 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.
Item Type: Article
Uncontrolled Keywords: Autophagy; breast cancer; carcinoma-associated fibroblast; cardiotrophin 1; tumor stroma
Divisions: Sabancı University Nanotechnology Research and Application Center
Depositing User: Devrim Gözüaçık
Date Deposited: 07 Sep 2023 12:25
Last Modified: 07 Sep 2023 12:25
URI: https://research.sabanciuniv.edu/id/eprint/47793

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