Interferon-ε is a tumour suppressor and restricts ovarian cancer

Marks, Zoe R. C.; Campbell, Nicole K.; Mangan, Niamh E.; Vandenberg, Cassandra J.; Gearing, Linden J.; Matthews, Antony Y.; Gould, Jodee; Tate, Michelle D.; Wray-McCann, Georgie; Ying, Le; Rosli, Sarah; Brockwell, Natasha K.; Parker, Belinda S.; Lim, San Sui; Bilandzic, Maree; Christie, Elizabeth L.; Stephens, Andrew; Geus, Eveline D. de; Wakefield, Matthew J.; Ho, Gwo-Yaw; McNally, Orla; Webb, PM; deFazio, Anna; Traficante, Nadia; Fereday, Sián; Bowes, Leanne; Hendley, Joy; McNeish, Iain A.; Bowtell, David D.L.; Weerd, Nicole A. de; Scott, Clare L.; Bourke, Nollaig M.; Hertzog, Paul J.

doi:10.1038/s41586-023-06421-w

Cited by 32 publications

(11 citation statements)

References 55 publications

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“…Alternatively, in Egyptian fruit bats interferon-ε might play a role in tissue homeostasis independent of classical interferon signaling 106 . Our work also entails a first comprehensive functional comparison of type-I and type-III epithelial interferon responses in bats, the latter of which are rapidly and strongly induced after virus infections and can confer antiviral immunity in bat organoids.…”

Section: Discussionmentioning

confidence: 99%

Reconstructing bat antiviral immunity using epithelial organoids

Kellner,

Zelger,

Monteil

et al. 2024

Preprint

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SummaryBats are remarkably resilient to viruses with pandemic potential. To resolve largely unknown molecular mechanisms governing their exceptional antiviral immunity, we established an organoid platform to model the entire respiratory airway and intestinal epithelium of the important viral reservoir speciesRousettus aegyptiacus(Egyptian fruit bat). These bat organoids exhibit an unexpected diversity of cell types and support replication of highly pathogenic zoonotic viruses including Marburg virus (MARV) and MERS-Coronavirus. Following virus infection, bat organoids unleash a strong interferon response, uniquely regulated through virus-dependent and virus-independent mechanisms. By contrast, MARV infected human organoids fail to induce an antiviral gene response and express pro-inflammatory cytokines after interferon stimulation, revealing important molecular differences between bats and humans with implications for lethal Marburg virus infections in primates. These data provide the most comprehensive organoid platform in bats to decode species-specific differences and uncover fundamental principles of bat disease resilience to emerging viruses with pandemic potential.

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Section: Discussionmentioning

confidence: 99%

Reconstructing bat antiviral immunity using epithelial organoids

Kellner,

Zelger,

Monteil

et al. 2024

Preprint

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“…This treatment suggestion is supported by a phase II study that combined cisplatin and alpha-2 interferon in non-small cell lung cancer, with a 30% response rate and acceptable toxicity 27 . Indeed, several approaches to increase IFN-I activity have been published recently, such as targeting macrophages 28 or IFN-epsilon 29 . As chemo-refractory patients currently do not have efficient treatment options, a clinical trial to test the efficacy of IFN-I modulation and platinum-based chemotherapy is warranted.…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Analysis Reveals the Attenuation of the Interferon Pathway as a Driver of Chemo-Refractory Ovarian Cancer

Afenteva,

Yu,

Rajavuori

et al. 2024

Preprint

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Ovarian high-grade serous carcinoma (HGSC) represents the deadliest gynecological malignancy, with 10-15% of patients exhibiting primary resistance to first-line chemotherapy. These primarily chemo-refractory patients have particularly poor survival outcomes, emphasizing the urgent need for developing predictive biomarkers and novel therapeutic approaches. Here, we show that interferon type I (IFN-I) pathway activity in cancer cells is a crucial determinant of chemotherapy response in HGSC. Through a comprehensive multi-omics analysis within the DECIDER observational trial (ClinicalTrials.gov identifierNCT04846933) cohort, we identified that chemo-refractory HGSC is characterized by diminished IFN-I and enhanced hypoxia pathway activities. Importantly, IFN-I pathway activity was independently prognostic for patient survival, highlighting its potential as a biomarker. Our results elucidate the heterogeneity of treatment response at the molecular level and suggest that augmentation of IFN-I response could enhance chemosensitivity in refractory cases. This study underscores the potential of the IFN-I pathway as a therapeutic target and advocates for the initiation of clinical trials testing external modulators of the IFN-I response, promising a significant stride forward in the treatment of refractory HGSC.

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“…This may indicate that maintaining adhesion and the integrity of the cytoskeleton contributes to the responder phenotype, and it is conceivable that this requires continuous protein translation. Additionally, responders showed an enrichment of interferon signalling, which aids anti-tumour immunity by stimulating immune cell function and also may be involved in controlling proliferation and progression in cancer cells [62–64]. Comparing the gene regulatory network of doublets in responders to non-responders showed that non-responders were enriched in the activity of core EMT activating TFs such as ZEB1/2, SNAI1/2, and TWIST1.…”

Section: Discussionmentioning

confidence: 99%

Physical cell-cell interactions regulate transcriptional programmes that control the responses of high grade serous ovarian cancer patients to therapy

Hameed,

Kolch,

Brennan

et al. 2024

Preprint

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The tumour microenvironment is composed of a complex cellular network involving cancer, stromal and immune cells in dynamic interactions. A large proportion of this network relies on direct physical interactions between cells, which may impact patient responses to clinical therapy. Doublets in scRNA-seq are usually excluded from analysis. However, they may represent directly interacting cells. To decipher the physical interaction landscape in relation to clinical prognosis, we inferred a physical cell-cell interaction (PCI) network from 'biological' doublets in a scRNA-seq dataset of approximately 18,000 cells, obtained from 7 treatment-naive ovarian cancer patients. Focusing on cancer-stromal PCIs, we uncovered molecular interaction networks and transcriptional landscapes that stratified patients in respect to their clinical responses to standard therapy. Good responders featured PCIs involving immune cells interacting with other cell types including cancer cells. Poor responders lacked immune cell interactions, but showed a high enrichment of cancer-stromal PCIs. To explore the molecular differences between cancer-stromal PCIs between responders and non-responders, we identified correlating gene signatures. We constructed ligand-receptor interaction networks and identified associated downstream pathways. The reconstruction of gene regulatory networks and trajectory analysis revealed distinct transcription factor (TF) clusters and gene modules that separated doublet cells by clinical outcomes. Our results indicate (i) that transcriptional changes resulting from PCIs predict the response of ovarian cancer patients to standard therapy, (ii) that immune reactivity of the host against the tumour enhances the efficacy of therapy, and (iii) that cancer-stromal cell interaction can have a dual effect either supporting or inhibiting therapy responses.

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Interferon-ε is a tumour suppressor and restricts ovarian cancer

Cited by 32 publications

References 55 publications

Reconstructing bat antiviral immunity using epithelial organoids

Reconstructing bat antiviral immunity using epithelial organoids

Multi-Omics Analysis Reveals the Attenuation of the Interferon Pathway as a Driver of Chemo-Refractory Ovarian Cancer

Physical cell-cell interactions regulate transcriptional programmes that control the responses of high grade serous ovarian cancer patients to therapy

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