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ORIGINAL RESEARCH article

Front. Bioinform.

Sec. Integrative Bioinformatics

Volume 5 - 2025 | doi: 10.3389/fbinf.2025.1669236

Spatial Heterogeneity Reveals an Evolutionary Signature Predicting Therapeutic Response and Clinical Outcomes in Hepatocellular Carcinoma

Provisionally accepted
Shangyi  LuoShangyi Luo1Li  LiuLi Liu1Yang  SunYang Sun2Jian  ShiJian Shi3Yajing  ZhangYajing Zhang4*
  • 1Fuzhou University, Fuzhou, China
  • 2Fujian Provincial Cancer Hospital, Fuzhou, China
  • 3Chongqing Medical University, Chongqing, China
  • 4Harbin Medical University, Harbin, China

The final, formatted version of the article will be published soon.

Introduction: Intra-tumoral heterogeneity is a prominent characteristic of hepatocellular carcinoma (HCC). However, it remains unexplored whether intra-tumoral transcriptomic differences can capture crucial information regarding HCC evolution and be utilized to derive a predictive signature for patient’s clinical trajectories. Methods: We quantified transcriptomic heterogeneity using four multiregional HCC cohorts comprising 172 samples from 37 patients, and validated transcriptomic heterogeneity and spatial dynamics using multiregional single-cell transcriptomic profiling of 110,817 cells from 34 liver specimens. The HCC evolutionary signature (HCCEvoSig) was developed and assessed across six cross-platform HCC cohorts. Results: Genes exhibiting high intra- and inter-tumor expression variation were significantly enriched in a gene set associated with HCC prognosis, from which we developed and validated a reproducible and robust transcriptomic signature, HCCEvoSig. Multiregional single-cell data confirmed the high intra- and inter-tumoral heterogeneity of HCCEvoSig genes across different cell types, and importantly, demonstrated that the dysregulation of HCCEvoSig genes exhibited a geospatially gradual transition from the non-tumor region to the tumor border and tumor core, as well as from non-malignant to malignant epithelial cells. HCCEvoSig showed significant positive associations with adverse features of HCC, and a high HCCEvoSig risk score predicted increased risks of disease progression and mortality, independent of established clinicopathological indices. Furthermore, HCCEvoSig outperformed 15 published signatures in discriminative ability and prognostic accuracy, particularly regarding 1-year survival rates. Notably, HCCEvoSig demonstrated predictive utility for responses to immunotherapy and trans-arterial chemoembolization. Additionally, we established a well-calibrated predictive nomogram that integrates HCCEvoSig and TNM stage to generate an individualized numerical probability of mortality. Conclusion: Our study reveals that regional transcriptional heterogeneity within tumors is substantial enough to capture survival signals, and the constructed and validated HCCEvoSig provides reliable prognostic information for HCC patients.

Keywords: Hepatocellular Carcinoma, multi-region sequencing, expression dynamics, tumor evolution, prognostication

Received: 19 Jul 2025; Accepted: 05 Aug 2025.

Copyright: © 2025 Luo, Liu, Sun, Shi and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Yajing Zhang, Harbin Medical University, Harbin, China

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