Multi-modal characterization of transcriptional programs that drive metastatic cascades to solid sites and ascites in ovarian cancer

Zhang, K.; Kahelin, E.; Marchi, G.; Lehtonen, O.; Salloum, S.; Lavikka, K.; Li, Y.; Dietlein, F.; Lahtinen, A.; Oikkonen, J.; Hietanen, S.; Hynninen, J.; Hakkinen, A.; Virtanen, A.; Hautaniemi, S.

doi:10.1101/2025.08.26.672372

bioRxiv · 10.1101/2025.08.26.672372

Multi-modal characterization of transcriptional programs that drive metastatic cascades to solid sites and ascites in ovarian cancer

Zhang, K.·Kahelin, E.·Marchi, G.·Lehtonen, O.·Salloum, S.·Lavikka, K.·Li, Y.·Dietlein, F.·Lahtinen, A.·Oikkonen, J.·Hietanen, S.·Hynninen, J.·Hakkinen, A.·Virtanen, A.·Hautaniemi, S.

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Abstract

Ovarian high-grade serous carcinoma (HGSC) is characterized by extensive intra-peritoneal dissemination and tumor heterogeneity. In the metastatic cascade, tumors utilize several transcriptional programs to translocate and survive in distant tissues. Here, we analyzed multi-modal, real-world data from 350 tumor samples across 160 patients with HGSC to identify transcriptional programs that drive intra-peritoneal metastasis and heterogeneity. We identified nine transcriptional programs, including those regulating epithelial-mesenchymal transition and immune modulation and cytoskeletal reorganization, which shape distinct metastatic trajectories to solid and ascitic environments and are associated to treatment response. Our results reveal pronounced intra-patient transcriptional heterogeneity, which in some cases surpassed inter-patient heterogeneity, highlighting the importance of multi-site sampling for accurate prognostication and combinatorial treatments in HGSC. Our extensive characterization offers novel insights into intra-peritoneal metastasis with significant prognostic implications, reveals histomorphological biomarkers for patient stratification and paves the way for innovative therapeutic strategies aimed at impairing cancer cell adaptability and limiting metastasis.

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Zhang, K., Kahelin, E., Marchi, G., Lehtonen, O., Salloum, S., Lavikka, K., Li, Y., Dietlein, F., Lahtinen, A., Oikkonen, J., Hietanen, S., Hynninen, J., Hakkinen, A., Virtanen, A., Hautaniemi, S.. 2025-08-27. Multi-modal characterization of transcriptional programs that drive metastatic cascades to solid sites and ascites in ovarian cancer. https://doi.org/10.1101/2025.08.26.672372

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