Multi-omics analysis reveals the attenuation of the interferon pathway as a driver of chemo-refractory ovarian cancer
Ovarian high-grade serous carcinoma (HGSC) is one of the deadliest gynecological malignancies, with 10%-15% of patients exhibiting primary resistance to first-line chemotherapy. To characterize the molecular drivers of chemo-refractoriness, we perform multi-omics profiling of treatment-naive biopsies from patients with refractory HGSC enrolled in the DECIDER observational trial. We demonstrate that chemo-refractory HGSC is characterized by diminished interferon type I (IFN-I) and enhanced hypoxia pathway activity, and baseline IFN-I activity in chemo-naive cancer is an independent prognostic factor. Single-cell RNA sequencing and spatial protein profiling analyses corroborate the importance of elevated IFN-I activity in response to chemotherapy. Importantly, in vitro experiments demonstrate that high levels of IFN-I signaling increase cell chemosensitivity to platinum in a cell-autonomous manner. Together, these findings indicate that the IFN-I pathway activity in HGSC cancer cells predicts response to first-line chemotherapy in HGSC, proposing the stimulation of the IFN-I response as a therapeutic strategy. The study is registered at ClinicalTrials.gov (NCT04846933).
Authors
- Matías Marín Falco (ORCID: https://orcid.org/0000-0002-6813-0050)
- Daria Afenteva (ORCID: https://orcid.org/0009-0000-9596-2832)
- Marina Salvadores (ORCID: https://orcid.org/0000-0002-7850-7691)
- Veli‐Matti Isoviita (ORCID: https://orcid.org/0000-0001-7329-8934)
- Daniela Ungureanu (ORCID: https://orcid.org/0000-0002-9314-4972)
- Jussi Taipale (ORCID: https://orcid.org/0000-0003-4204-0951)
- Kari Lavikka (ORCID: https://orcid.org/0000-0002-4163-4945)
- Sampsa Hautaniemi (ORCID: https://orcid.org/0000-0002-7749-2694)
- Alexandra Lahtinen (ORCID: https://orcid.org/0000-0001-7179-2680)
- Rong Yu (ORCID: https://orcid.org/0000-0002-8488-0417)
- Inga-Maria Launonen (ORCID: https://orcid.org/0000-0002-4548-9650)
- Giulia Micoli (ORCID: https://orcid.org/0009-0003-9541-8177)
- Johanna Hynninen (ORCID: https://orcid.org/0000-0002-0854-7225)
- Sanaz Jamalzadeh (ORCID: https://orcid.org/0000-0002-6425-9455)
- Giovanni Marchi (ORCID: https://orcid.org/0000-0001-9513-1123)
- Inderpreet Sur (ORCID: https://orcid.org/0000-0001-5787-1040)
- Kaiyang Zhang (ORCID: https://orcid.org/0000-0002-0470-9581)
- Erdoğan Pekcan Erkan (ORCID: https://orcid.org/0000-0001-9287-4773)
- Anni Virtanen (ORCID: https://orcid.org/0000-0002-7467-8434)
- Jaana Oikkonen (ORCID: https://orcid.org/0000-0002-1063-2736)
- Anna Vähärautio (ORCID: https://orcid.org/0000-0003-4721-3954)
- Anniina Färkkilä (ORCID: https://orcid.org/0000-0002-3558-6617)
- Sakari Hietanen (ORCID: https://orcid.org/0000-0003-4734-4743)
- Anna Rajavuori (ORCID: https://orcid.org/0000-0003-4331-5419)
- Anna Pirttikoski (ORCID: https://orcid.org/0009-0007-8825-8004)
- Taru Muranen (ORCID: https://orcid.org/0000-0002-5895-1808)
- Yilin Li (ORCID: https://orcid.org/0000-0001-9408-6738)
Institutions
- University of Helsinki (FI)
- University of Turku (FI)
- Turku University Hospital (FI)
- Karolinska Institutet (SE)
- Institute for Research in Biomedicine (ES)
- Institute for Molecular Medicine Finland (FI)
- University of Oulu (FI)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102316
- Citations
- 6
- Primary Topic
- Ovarian cancer diagnosis and treatment
- Type
- article
- Field-Weighted Citation Impact
- 10.19
Funders
- Gilead Sciences
- European Commission
- Cancerfonden
- Vetenskapsrådet
- China Scholarship Council
- Orionin Tutkimussäätiö
- Syöpäsäätiö