Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer

Yutaro Mori; Yoshie Okimoto; Hiroaki Sakai; Yusuke Kanda; Hirokazu Ohata; Daisuke Shiokawa; Mikiko Suzuki; Hiroshi Yoshida; Haruka Ueda; Tomoyuki Sekizuka; Ryo Tamura; Kaoru Yamawaki; Tatsuya Ishiguro; Raul Nicolas Mateos; Yuichi Shiraishi; Yasushi Yatabe; Akinobu Hamada; Kosuke Yoshihara; Takayuki Enomoto; Koji Okamoto

doi:10.1016/j.xcrm.2024.101532

Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer

Cell Rep Med. 2024 Apr 23:101532. doi: 10.1016/j.xcrm.2024.101532. Online ahead of print.

Authors

Yutaro Mori¹, Yoshie Okimoto², Hiroaki Sakai², Yusuke Kanda², Hirokazu Ohata², Daisuke Shiokawa³, Mikiko Suzuki⁴, Hiroshi Yoshida⁵, Haruka Ueda⁶, Tomoyuki Sekizuka⁶, Ryo Tamura⁶, Kaoru Yamawaki⁶, Tatsuya Ishiguro⁶, Raul Nicolas Mateos⁷, Yuichi Shiraishi⁷, Yasushi Yatabe⁵, Akinobu Hamada⁴, Kosuke Yoshihara⁶, Takayuki Enomoto⁶, Koji Okamoto⁸

Affiliations

¹ Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan; Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan.
² Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan.
³ Ehime University Hospital Translational Research Center, Shitsukawa, Toon, Ehime 791-0295, Japan.
⁴ Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
⁵ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
⁶ Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan.
⁷ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
⁸ Advanced Comprehensive Research Organization, Teikyo University, Tokyo 173-0003, Japan. Electronic address: okamoto.kouji.dm@teikyo-u.ac.jp.

PMID: 38670097
DOI: 10.1016/j.xcrm.2024.101532

Abstract

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

Keywords: HIF-1α; PDGF; cancer-associated fibroblasts; chemoresistant niche; ovarian clear cell carcinoma.