Dissecting residual disease in spheroids reveals pan-cancer persistence signatures and a therapeutic window for oncolytic viruses.

Authors

Clara Fauveau, Emily Lawendy, Jules Deforges, Sandrine Cochin, Baptiste Moreau, Jean-Marc Balloul, Philippe Erbs, Shreyansh Jain, Gilles Laverny, PERSIST-SEQ Consortium

Published in

Molecular therapy. Oncology. Volume 34. Issue 3. Pages 201279. Sep 17, 2026. Epub Jun 19, 2026.

Abstract

Drug resistance remains a major burden in clinical care, often emerging from a subpopulation of cells in a drug-tolerant state. In this study, we aimed to characterize the transcriptional features of persistent non-small cell lung cancer (NSCLC) cells following cisplatin-pemetrexed chemotherapy and explore the therapeutic potency of oncolytic viruses to eliminate these cells. We established a 3D spheroid model of NSCLC and applied long-term chemotherapy to induce a reversible, non-proliferative persistent state associated with lower sensitivity to treatment. Single-cell RNA sequencing coupled with comparative analysis of multiple human datasets sheds light on a core transcriptional signature of persistence. This signature was enriched in patient-derived minimal residual disease (MRD) datasets, highlighting the clinical relevance of persistent preclinical models. Furthermore, transcriptomic analyses suggested a vulnerability of persister cells to oncolytic viruses, a finding validated in spheroid and patient-derived organoids. Altogether, these results define a conserved persistence signature and support the use of virotherapy as a promising option to target MRD.

PMID:
42438683
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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