Choi, Kyoung-Min Kim, Boram Lee, Su-Min Han, Jisoo Bae, Ha-Song Han, Su-Bhin Lee, Dagyeong Ham, In-Hye Hur, Hoon Kim, Eunjung Kim, Jae-Young 2024-01-19T08:00:37Z 2024-01-19T08:00:37Z 2024-01-18 2024-01 1478-811X https://pubs.kist.re.kr/handle/201004/112946 BackgroundCancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC.MethodsAlteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay.ResultsWe found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model.ConclusionsThis study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC.DC5ErEG73tsyg3F8WfE1xiVideo AbstractConclusionsThis study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC.DC5ErEG73tsyg3F8WfE1xiVideo Abstract English BioMed Central Characterization of gastric cancer-stimulated signaling pathways and function of CTGF in cancer-associated fibroblasts Article 10.1186/s12964-023-01396-7 1 Cell Communication and Signaling, v.22, no.1 Cell Communication and Signaling 22 1 Y scie scopus 001135382400010 2-s2.0-85181246166 Cell Biology Cell Biology Article TISSUE-GROWTH-FACTOR EPITHELIAL-MESENCHYMAL TRANSITION PHASE-II TRIAL BREAST-CANCER STROMAL MYOFIBROBLASTS CELL EXPRESSION ACTIVATION TRASTUZUMAB INVASION Cancer-associated fibroblasts (CAFs) Tumor microenvironment (TME) Gastric cancer (GC) Connective tissue growth factor (CTGF)