MET inhibition exploits conserved regulatory dependencies in malignant rhabdoid tumors
- 1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
Abstract
Malignant rhabdoid tumors (MRTs) are lethal, yet genomically simple childhood cancers characterised by universal SWI/SNF dysregulation. Despite this shared molecular framework, the regulatory programs sustaining MRTs and how they wire actionable dependencies, remain poorly defined. Here, we integrated single-cell multi-omic profiling and spatial transcriptomics across anatomically and molecularly diverse MRTs, generating a comprehensive multimodal MRT dataset at single-cell resolution. We leveraged this resource to identify candidate tumor-specific dependencies, which were subsequently functionally validated in vitro and in vivo in matched patient-derived models. We found that distinct malignant subpopulations are spatially patterned in complex environmentally shaped topologies, consistent with reciprocal interactions with stromal and immune compartments contributing to intratumoral transcriptional diversity. We identified recurrent transcriptional metaprograms conserved across patients and molecular subtypes, including a previously undescribed shared core rhabdoid program, as well as a metaprogram characterized by extracellular matrix interactions, and preferentially localized in tumor-stroma intermixed neighborhoods, supporting identification of niche conditioning cues. Mechanistically, we identified regulatory wiring driving these metaprograms, with the core shared rhabdoid programme coordinated by a circuit centred on TCF12, ZNF148 and CHD2. Guided by target nominations from our integrated analyses, we performed a curated drug screen using patient-derived MRT models and validated HGF/MET signaling as a selective vulnerability in extrarenal rhabdoid tumors. Pharmacologic MET inhibition was cytotoxic in sensitive models and induced a complete response in vivo using a clinically approved compound. Importantly, MET expression in primary tumors correlated with response, supporting biomarker-guided patient stratification for immediate clinical translation. Collectively, our findings define the molecular architecture of MRTs, reveal conserved regulatory programs beyond anatomical and molecular subtypes, and highlight a targetable signaling axis with immediate translational potential, establishing a framework for precision therapy in this lethal pediatric malignancy.
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BibTeX
@misc{sentis2026inhibition,
title = {{MET inhibition exploits conserved regulatory dependencies in malignant rhabdoid tumors}},
author = {I. Sentis and A. Cebria-Xart and Q. Rovira and E. Melon-Ardanaz and C. J. Rodriguez Hernandez and S. Morabito and A. Caballe and I. Ruano and A. Urpi and M. Caballero and S. Garcia Palomino and E. Rodriguez and D. Maspero and G. Caratu and A. Onieva and D. Marchese and M. Ruiz and P. Lorden and I. Ramos and C. E. Lavarino and A. Castaneda and A. Pascual-Reguant and J. Mora and J. C. Nieto and H. Heyn and A. Avgustinova},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763704},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763704v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - MET inhibition exploits conserved regulatory dependencies in malignant rhabdoid tumors
AU - I. Sentis
AU - A. Cebria-Xart
AU - Q. Rovira
AU - E. Melon-Ardanaz
AU - C. J. Rodriguez Hernandez
AU - S. Morabito
AU - A. Caballe
AU - I. Ruano
AU - A. Urpi
AU - M. Caballero
AU - S. Garcia Palomino
AU - E. Rodriguez
AU - D. Maspero
AU - G. Caratu
AU - A. Onieva
AU - D. Marchese
AU - M. Ruiz
AU - P. Lorden
AU - I. Ramos
AU - C. E. Lavarino
AU - A. Castaneda
AU - A. Pascual-Reguant
AU - J. Mora
AU - J. C. Nieto
AU - H. Heyn
AU - A. Avgustinova
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763704
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763704v1
AB - Malignant rhabdoid tumors (MRTs) are lethal, yet genomically simple childhood cancers characterised by universal SWI/SNF dysregulation. Despite this shared molecular framework, the regulatory programs sustaining MRTs and how they wire actionable dependencies, remain poorly defined. Here, we integrated single-cell multi-omic profiling and spatial transcriptomics across anatomically and molecularly diverse MRTs, generating a comprehensive multimodal MRT dataset at single-cell resolution. We leveraged this resource to identify candidate tumor-specific dependencies, which were subsequently functionally validated in vitro and in vivo in matched patient-derived models. We found that distinct malignant subpopulations are spatially patterned in complex environmentally shaped topologies, consistent with reciprocal interactions with stromal and immune compartments contributing to intratumoral transcriptional diversity. We identified recurrent transcriptional metaprograms conserved across patients and molecular subtypes, including a previously undescribed shared core rhabdoid program, as well as a metaprogram characterized by extracellular matrix interactions, and preferentially localized in tumor-stroma intermixed neighborhoods, supporting identification of niche conditioning cues. Mechanistically, we identified regulatory wiring driving these metaprograms, with the core shared rhabdoid programme coordinated by a circuit centred on TCF12, ZNF148 and CHD2. Guided by target nominations from our integrated analyses, we performed a curated drug screen using patient-derived MRT models and validated HGF/MET signaling as a selective vulnerability in extrarenal rhabdoid tumors. Pharmacologic MET inhibition was cytotoxic in sensitive models and induced a complete response in vivo using a clinically approved compound. Importantly, MET expression in primary tumors correlated with response, supporting biomarker-guided patient stratification for immediate clinical translation. Collectively, our findings define the molecular architecture of MRTs, reveal conserved regulatory programs beyond anatomical and molecular subtypes, and highlight a targetable signaling axis with immediate translational potential, establishing a framework for precision therapy in this lethal pediatric malignancy.
ER -