Multi-tissue modeling of BRCA cancers using iPSC-derived organoids platform

Germline pathogenic mutations in the BRCA1 and BRCA2 genes (BRCA1/2mut) are the strongest genetic risk factors for high-grade serous ovarian cancer, and estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC). Pathogenic variants in these genes are implicated in about 15% of women with heritable risks of these cancers. Moreover, BRCA2 mut are associated with increased risk of ER+ breast cancer and aggressive prostate cancer in men. Precise risk estimates for BRCA1/2 mut that affect different cancer types are crucial to evaluate treatments and enhance drug sensitivity. Patient-specific induced pluripotent stem cell (iPSC) methods create opportunities to model human diseases in vitro. iPSCs derived from patients with known genetic mutations carry the patient's unique genetic background, to provide platforms for studying the functional effects of specific genes. Several inherited disease models created from iPSCs have successfully replicated high-risk cancers. This study aimed to utilize iPSC-based modeling to investigate the functional impact of pathogenic BRCA1/2 mut on early-stage phenotypes and genomic alterations that contribute to cancer progression. Methods: We generated iPSC from both BRCA1/2 mut carriers' women and BRCA2 mut carrier male. From female BRCA1/2 mut , we have established iPSC-derived organoid models of ovarian cancer -OC-(fallopian tube epithelium, FTE) and breast cancer -BC-(mammary gland epithelium, MGE) and from male BRCA2 mut prostate cancer-PC. Results: Following differentiation into FT organoids, both heterozygous BRCA1/2 mut models show specific cellular abnormalities - neoplastic transformation, expression of cancer-specific biomarkers - compared to BRCA WT controls. ER+ BC and TNBC models revealed that following differentiation into MG organoids: models from heterozygous BRCA1/2 mut carriers conferred a neoplastic phenotype reminiscent of a ductal carcinoma in situ (DCIS) compared to BRCA WT controls. Notably, the development of DCIS in BRCA2 mut carriers was dependent on estrogen (E2) exposure, while in BRCA1 mut carriers, it was independent of hormonal influences; this may suggest that BRCA haploinsufficiency contributes to the observed phenotype. PC models from BRCA2 mut subjects exhibit abnormalities reminiscent of early-stage neoplastic development. Importantly, prostate organoids with combinations of BRCA2 mut and PTEN alterations exhibited more aggressive PC phenotypes compared to BRCA2 mut and BRCA WT organoids alone, and shared genomic signatures with primary aggressive PC. Conclusion and Impact . iPSC-derived multi-tissue organoid platform can accurately replicate BRCA1/2 mut and BRCA WT precursor tissues. This allows cancer to evolve in a dish, making it an ideal model for mechanistic studies and screening approaches to identify novel drug targets.