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bioRxiv2024

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

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 identifier NCT04846933) 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.

cancer biology↗

bioRxiv2016

Mice deficient of Myc super-enhancer region reveal a differential control mechanism between normal and pathological growth

The gene desert upstream of the Myc oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50 to 80% decrease in MYC expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but not in vivo. These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.

cancer biology↗