PMID- 36919193 OWN - NLM STAT- MEDLINE DCOM- 20230413 LR - 20230529 IS - 2523-3548 (Electronic) IS - 2523-3548 (Linking) VI - 43 IP - 4 DP - 2023 Apr TI - Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib. PG - 455-479 LID - 10.1002/cac2.12414 [doi] AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC). METHODS: We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression-free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis. RESULTS: Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo. CAF-derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin-protein kinase C-alpha (PKCalpha) signaling pathway and promoted epithelial-to-mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS (P = 0.026) and OS (P = 0.047) in patients with advanced HCC after TKI treatment. CONCLUSIONS: CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction. CI - (c) 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center. FAU - Eun, Jung Woo AU - Eun JW AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. FAU - Yoon, Jung Hwan AU - Yoon JH AUID- ORCID: 0000-0001-7770-2965 AD - Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. FAU - Ahn, Hye Ri AU - Ahn HR AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. AD - Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea. FAU - Kim, Seokhwi AU - Kim S AD - Department of Pathology, Ajou University School of Medicine, Suwon, South Korea. FAU - Kim, Young Bae AU - Kim YB AD - Department of Pathology, Ajou University School of Medicine, Suwon, South Korea. FAU - Lim, Su Bin AU - Lim SB AD - Department of Biochemistry & Molecular Biology, Ajou University School of Medicine, Suwon, South Korea. FAU - Park, Won AU - Park W AD - The Moagen, Inc, Daejeon, South Korea. FAU - Kang, Tae Wook AU - Kang TW AD - The Moagen, Inc, Daejeon, South Korea. FAU - Baek, Geum Ok AU - Baek GO AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. FAU - Yoon, Moon Gyeong AU - Yoon MG AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. FAU - Son, Ju A AU - Son JA AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. AD - Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea. FAU - Weon, Ji Hyang AU - Weon JH AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. AD - Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea. FAU - Kim, Soon Sun AU - Kim SS AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. FAU - Cho, Hyo Jung AU - Cho HJ AUID- ORCID: 0000-0003-4792-8335 AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. FAU - Cheong, Jae Youn AU - Cheong JY AD - Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230314 PL - United States TA - Cancer Commun (Lond) JT - Cancer communications (London, England) JID - 101723675 RN - 9ZOQ3TZI87 (Sorafenib) RN - EE083865G2 (lenvatinib) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 106441-73-0 (Osteopontin) SB - IM MH - Humans MH - Sorafenib/therapeutic use MH - *Carcinoma, Hepatocellular/pathology MH - *Cancer-Associated Fibroblasts/metabolism/pathology MH - Phosphatidylinositol 3-Kinases MH - Osteopontin/therapeutic use MH - *Liver Neoplasms/pathology PMC - PMC10091107 OTO - NOTNLM OT - drug resistance OT - epithelial-to-mesenchymal transition OT - hepatocellular carcinoma OT - secreted phosphoprotein 1 COIS- The authors have declared that no conflict of interest exists. EDAT- 2023/03/16 06:00 MHDA- 2023/04/13 06:43 PMCR- 2023/03/14 CRDT- 2023/03/15 01:53 PHST- 2022/12/13 00:00 [revised] PHST- 2022/08/01 00:00 [received] PHST- 2023/03/06 00:00 [accepted] PHST- 2023/04/13 06:43 [medline] PHST- 2023/03/16 06:00 [pubmed] PHST- 2023/03/15 01:53 [entrez] PHST- 2023/03/14 00:00 [pmc-release] AID - CAC212414 [pii] AID - 10.1002/cac2.12414 [doi] PST - ppublish SO - Cancer Commun (Lond). 2023 Apr;43(4):455-479. doi: 10.1002/cac2.12414. Epub 2023 Mar 14.