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Multiomics analysis revealed proteomic subtyping of hepatocellular carcinoma guide the precise therapy of sorafenib

ABSTRACT: Multiomics analysis revealed proteomic subtyping of hepatocellular carcinoma guide the precise therapy of sorafenib

ORGANISM(S): Homo Sapiens

SUBMITTER: Xiaolong Liu

PROVIDER: PXD046519 | iProX | Mon Oct 30 00:00:00 GMT 2023

REPOSITORIES: iProX

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Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.

Xing Xiaohua X Hu En E Ouyang Jiahe J Zhong Xianyu X Wang Fei F Liu Kaixin K Cai Linsheng L Zhou Yang Y Wang Yingchao Y Chen Geng G Li Zhenli Z Wu Liming L Liu Xiaolong X

Cell reports. Medicine 20231212 12

Patients with hepatocellular carcinoma (HCC) at the same clinical stage can have extremely different prognoses, and molecular subtyping provides an opportunity for individualized precision treatment. In this study, genomic, transcriptomic, proteomic, and phosphoproteomic profiling of primary tumor tissues and paired para-tumor tissues from HCC patients (N = 160) are integrated. Proteomic profiling identifies three HCC subtypes with different clinical prognosis, which are validated in three publi ...[more]

PMID: 38091986

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Dataset Information

Multiomics analysis revealed proteomic subtyping of hepatocellular carcinoma guide the precise therapy of sorafenib

Publications

Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy.

Similar Datasets

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