Proteogenomic characterization of molecular and cellular targets for treatment-resistant subtypes in locally advanced cervical cancers
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 CXCL1<sup>high</sup> fibroblasts) characterized the immune-hot Sub3 enriched with MUC5AC<sup>high</sup> epithelial cells (ECs). Increased epithelial-mesenchymal-transition (EMT) and ECM remodeling characterized the immune-cold squamous Sub5 enriched with PGK1 and CXCL10<sup>high</sup> 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 FCGR3B<sup>high</sup> macrophages) could cause suppression of T-cell activation in Sub5. Increased O-linked glycosylation of mucin characterized adeno-LACC Sub6 enriched with MUC5AC<sup>high</sup> 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.
Authors
- Ja‐Lok Ku (ORCID: https://orcid.org/0000-0002-7090-537X)
- Yourae Shin (ORCID: https://orcid.org/0000-0002-3274-726X)
- Keehoon Jung (ORCID: https://orcid.org/0000-0002-2199-5292)
- Su‐Hwan Kim (ORCID: https://orcid.org/0000-0001-5337-3335)
- Young‐Ki Bae
- Chong Woo Yoo
- Inamul Hasan Madar (ORCID: https://orcid.org/0000-0002-6913-1776)
- Jingi Bae (ORCID: https://orcid.org/0000-0001-8638-3513)
- Daehee Hwang (ORCID: https://orcid.org/0000-0002-7553-0044)
- Soo Young Cho (ORCID: https://orcid.org/0000-0002-2960-9878)
- Seunghoon Back
- Ki Seok Park (ORCID: https://orcid.org/0000-0001-5235-6365)
- Jong-Kwang Kim (ORCID: https://orcid.org/0000-0001-9290-0820)
- Chaewon Kang
- Duk Ki Kim (ORCID: https://orcid.org/0000-0002-7433-907X)
- Geon Woo Park
- Dong Hoon Shin (ORCID: https://orcid.org/0000-0001-8032-1266)
- Dowoon Nam (ORCID: https://orcid.org/0000-0002-8085-6030)
- Sujin Kim (ORCID: https://orcid.org/0000-0002-0813-1086)
- Sang‐Won Lee (ORCID: https://orcid.org/0000-0002-5042-0084)
- Sang Jin Lee (ORCID: https://orcid.org/0000-0002-3899-1909)
- Sang Soo Kim (ORCID: https://orcid.org/0000-0002-4079-2503)
- Hye-Jin Shin
- Juhee Jeong (ORCID: https://orcid.org/0000-0003-4732-147X)
- Eun-Kyung Hong
- Hokeun Kim (ORCID: https://orcid.org/0000-0002-8671-5255)
- Eunsoo Jung (ORCID: https://orcid.org/0000-0003-2192-5603)
- Ji Young Kang (ORCID: https://orcid.org/0000-0003-4754-602X)
- Do Young Hyeon
- Joo‐Young Kim
- Hye Jung Baek
- Wonyoung Choi
- Myong Cheol Lim (ORCID: https://orcid.org/0000-0001-8964-7158)
Institutions
- Seoul National University (KR)
- Korea University (KR)
- National Cancer Center (KR)
Publication Details
- Journal
- Molecular Cancer
- Published
- 2025-03-14
- DOI
- https://doi.org/10.1186/s12943-025-02256-3
- Citations
- 10
- Primary Topic
- Molecular Biology Techniques and Applications
- Type
- article
- Field-Weighted Citation Impact
- 8.06