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Mol. Cancer, Mar 14 2025, 24 (1) | https://doi.org/10.1186/s12943-025-02256-3
Proteogenomic characterization of molecular and cellular targets for treatment-resistant subtypes in locally advanced cervical cancers
Do Young Hyeon 1†, Dowoon Nam 2†, Hye-Jin Shin 3†, Juhee Jeong 4†, Eunsoo Jung 1†, Soo Young Cho 3, Dong Hoon Shin 3, Ja-Lok Ku 5, Hye Jung Baek 3, Chong Woo Yoo 3, Eun-Kyung Hong 3, Myong Cheol Lim 3, Sang-Jin Lee 3, Young-Ki Bae 3, Jong Kwang Kim 3, Jingi Bae 2, Wonyoung Choi 3, Su-Jin Kim 2, Seunghoon Back 2, Chaewon Kang 2, Inamul Hasan Madar 2, Hokeun Kim 2, Suhwan Kim 2, Duk Ki Kim 4, Jihyung Kang 4, Geon Woo Park 4, Ki Seok Park 4, Yourae Shin 1, Sang Soo Kim 3*, Keehoon Jung 4,6*, Daehee Hwang 1*, Sang-Won Lee 2* and Joo-Young Kim 3*
1School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
2Department of Chemistry and Center for Proteogenome Research, Korea University, Seoul 02843, Republic of Korea.
3Research Institute and Hospital, National Cancer Center, Goyang 10408, Republic of Korea.
4Department of Anatomy and Cell Biology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
5Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
6Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea.
†Do Young Hyeon, Dowoon Nam, Hye-Jin Shin, Juhee Jeong, Eunsoo Jung contributed equally to this work.
*Corresponding authors: correspondence to Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang-Won Lee or Joo-Young Kim
*Corresponding authors: correspondence to Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang-Won Lee or Joo-Young Kim
Abstract
We report proteogenomic analysis of locally advanced cervical cancer (LACC). Exome-seq data revealed predominant alterations of keratinization-TP53 regulation and O-glycosylation-TP53 regulation axes in squamous and adeno-LACC, respectively, compared to in early-stage cervical cancer. Integrated clustering of mRNA, protein, and phosphorylation data identified six subtypes (Sub1-6) of LACC among which Sub3, 5, and 6 showed the treatment-resistant nature with poor local recurrence-free survival. Elevated immune and extracellular matrix (ECM) activation mediated by activated stroma (PDGFD and CXCL1high fibroblasts) characterized the immune-hot Sub3 enriched with MUC5AChigh epithelial cells (ECs). Increased epithelial-mesenchymal-transition (EMT) and ECM remodeling characterized the immune-cold squamous Sub5 enriched with PGK1 and CXCL10high ECs. We further demonstrated that CIC mutations could trigger EMT activation by upregulating ETV4, and the elevation of the immune checkpoint PVR and neutrophil-like myeloid-derived suppressive cells (FCN1 and FCGR3Bhigh macrophages) could cause suppression of T-cell activation in Sub5. Increased O-linked glycosylation of mucin characterized adeno-LACC Sub6 enriched with MUC5AChigh ECs. These results provide a battery of somatic mutations, cellular pathways, and cellular players that can be used to predict treatment-resistant LACC subtypes and can serve as potential therapeutic targets for these LACC subtypes.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-17)
- 국내 연구진
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