ORIGINAL RESEARCH article
Front. Bioinform.
Sec. Genomic Analysis
PAN-CANCER ANALYSES IDENTIFY ONCOGENIC DRIVERS, EXPRESSION SIGNATURES, AND THERAPEUTIC VULNERABILITIES IN RHO GTPase PATHWAY GENES
Provisionally accepted
- 1Cancer Research Center, Spanish National Research Council (CSIC), Madrid, Salamanca, Spain
- 2Universidad de Salamanca, Salamanca, Spain
- 3Universidad de Oviedo, Oviedo, Spain
- 4Consorcio Centro de Investigacion Biomedica en Red, Madrid, Spain
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
RHO family GTPases are key regulators of cancer-related processes such as cytoskeletal dynamics, cell migration, proliferation, and survival. Despite this, a comprehensive understanding of RHO signaling alterations across tumors is still lacking. Here, we present a pan-cancer analysis of 484 genes encoding RHO GTPases, regulators, proximal effectors, distal downstream signaling elements, and components of their proximal interactomes using data from over 10,000 tumor samples and 33 tumor types present in The Cancer Genome Atlas (TCGA). In addition, we have utilized available data from genome-wide functional dependency screens performed in more than 1,000 gene-edited cancer cell lines. This study has uncovered positively selected mutations in both well-known and previously uncharacterized RHO pathway genes. Transcriptomic profiling reveals widespread and tumor-specific differential expression patterns, some of them correlating with copy number changes. Interestingly, certain regulators exhibit consistent expression profiles across tumors opposite to those predicted from their canonical roles. Coexpression and gene set enrichment analyses highlight coordinated transcriptional programs involving some RHO GTPase pathway genes and their linkage to key cancer hallmarks, including extracellular matrix reorganization, cell motility, cell cycle progression, cell survival, and immune modulation. Functional screens further identify context-specific dependencies on several deregulated RHO GTPase pathway genes. Altogether, this study provides a comprehensive map of RHO GTPase pathway alterations in cancer and identifies new oncogenic drivers, expression-based signatures, and therapeutic vulnerabilities that could guide future mechanistic and translational research in this area.
Keywords: Rho GTPases, Cancer genomics, Signal Transduction, tumor suppressors, Oncogenes, Functional Genomics, CRISPR screens, somatic mutations
Received: 20 Nov 2025; Accepted: 24 Nov 2025.
Copyright: © 2025 Fernandez, Lorenzo-Martin, Quesada and Bustelo. 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: Xose R. Bustelo
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.