A single-nucleus multimodal framework reveals epigenomic priming of chemoresistant states in ovarian cancer

Landais, Y.; Bertorello, J.; Puerto, M.; Kahn, A.; Simon, B.; Roehrig, A.; Durand, A.; Quatredeniers, M.; Lamy, C.; Delville, M.; Richard, M.; Laas, E.; Pouget, N.; Dumas, S.; Feron, J.-G.; Fourchotte, V.; Bonneau, C.; Cockenpot, V.; Kamal, M.; Lecuru, F.; Le Tourneau, C.; Vallot, C.

doi:10.64898/2025.12.04.692102

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bioRxiv · 10.64898/2025.12.04.692102

A single-nucleus multimodal framework reveals epigenomic priming of chemoresistant states in ovarian cancer

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Abstract

Non-genetic intratumor heterogeneity (ITH) drives therapeutic failure in cancer, yet its clinical monitoring remains challenging. We develop a multimodal single-nucleus framework that simultaneously profiles transcriptional and histone modification landscapes from frozen biopsies. Applied to longitudinal samples from 16 patients with high-grade serous ovarian cancer (HGSOC), this approach reveals reproducible tumor evolution under chemotherapy: proliferative and interferon-responsive states are lost, while those associated with TNF- and epithelial-mesenchymal transition (EMT) expand. Chromatin profiling shows that these chemoresistant programs are epigenetically primed through H3K4me1 marks before treatment and nominates transcription-factor drivers, including ZBTB7A. Non-genetic baseline tumor composition predicts survival, and fibroblast remodeling parallels malignant adaptation. These findings establish a clinically scalable strategy for mapping functional ITH and identify epigenomic priming as a determinant of therapeutic failure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/692102v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@432524org.highwire.dtl.DTLVardef@3b7843org.highwire.dtl.DTLVardef@54a2eforg.highwire.dtl.DTLVardef@95273d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Landais, Y., Bertorello, J., Puerto, M., Kahn, A., Simon, B., Roehrig, A., Durand, A., Quatredeniers, M., Lamy, C., Delville, M., Richard, M., Laas, E., Pouget, N., Dumas, S., Feron, J.-G., Fourchotte, V., Bonneau, C., Cockenpot, V., Kamal, M., Lecuru, F., Le Tourneau, C., Vallot, C.. 2025-12-08. A single-nucleus multimodal framework reveals epigenomic priming of chemoresistant states in ovarian cancer. https://doi.org/10.64898/2025.12.04.692102

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