PO.TB07.01 · 肿瘤生物学

利用iPSC来源类器官平台对BRCA癌症进行多组织建模

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

编号 840 展板 19 时间 4/19 02:00–05:00 区域 Section 33 主讲 nur yucer

分会场 Stem Cell Plasticity and Lineage Reprogramming in Cancer

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作者与单位 Authors & Affiliations

Nur Yucer¹, Alyssa Okimoto², Subash Dhungana¹, Dean Bacich¹, Rebecca Webster¹, Beatriz German Falcon³, Michelle Jones⁴, Sarah Parker⁴, Bobbie Jo Rimel⁵, Beth Y. Karlan⁶, Leigh Ellis³, Matthew Freedman⁷, Robin J. Leach⁸, Xiaojiang Cui⁴, Kate Lawrenson¹, Simon Gayther¹

¹Medicine, Center for Inherited Oncogenesis, UT Health San Antonio, Long School of Medicine,, San Antonio, TX,²Center for Inherited Oncogenesis, UT Health San Antonio, Long School of Medicine,, San Antonio, TX,³Department of Surgery, Center for Prostate Disease Research, Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences,, Bethesda, MD,⁴Cedars-Sinai Medical Center, Los Angeles, CA,⁵University of Washington Department of Obstetrics and Gynecology, Seattle, WA,⁶UCLA David Geffen School of Medicine, Los Angeles, CA,⁷Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA,⁸UT Health Science Ctr. at San Antonio, San Antonio, TX

摘要 Abstract

中文摘要

BRCA1和BRCA2基因的种系致病突变（BRCA1/2mut）是高级别浆液性卵巢癌以及雌激素受体阳性（ER+）和三阴性乳腺癌（TNBC）最强的遗传风险因素。这些基因的致病变异与约15%具有这些癌症遗传易感风险的女性相关。此外，BRCA2 mut与男性ER+乳腺癌风险增加和侵袭性前列腺癌相关。对影响不同癌症类型的BRCA1/2 mut进行精确的风险评估，对于评价治疗方法和提高药物敏感性至关重要。患者特异性诱导多能干细胞（iPSC）方法为体外模拟人类疾病创造了机会。来自已知遗传突变患者的iPSC携带患者独特的遗传背景，为研究特定基因的功能效应提供了平台。已有多个由iPSC构建的遗传性疾病模型成功再现了高风险癌症。本研究旨在利用基于iPSC的建模，研究致病性BRCA1/2 mut对早期表型和促成癌症进展的基因组改变的功能影响。方法：我们从BRCA1/2 mut携带者女性和BRCA2 mut携带者男性中生成了iPSC。从女性BRCA1/2 mut，我们建立了iPSC来源的卵巢癌（OC，输卵管上皮，FTE）和乳腺癌（BC，乳腺上皮，MGE）类器官模型，从男性BRCA2 mut建立了前列腺癌（PC）模型。结果：分化为FT类器官后，与BRCA WT对照相比，两种杂合BRCA1/2 mut模型均显示出特定的细胞异常——肿瘤性转化、癌症特异性生物标志物表达。ER+ BC和TNBC模型显示，分化为MG类器官后：与BRCA WT对照相比，来自杂合BRCA1/2 mut携带者的模型呈现出类似导管原位癌（DCIS）的肿瘤性表型。值得注意的是，BRCA2 mut携带者中DCIS的发生依赖于雌激素（E2）暴露，而在BRCA1 mut携带者中则不受激素影响；这可能提示BRCA单倍剂量不足促成了所观察到的表型。来自BRCA2 mut受试者的PC模型表现出类似早期肿瘤性发育的异常。重要的是，与单独的BRCA2 mut和BRCA WT类器官相比，具有BRCA2 mut和PTEN改变组合的前列腺类器官表现出更具侵袭性的PC表型，并与原发性侵袭性PC共享基因组特征。结论与意义：iPSC来源的多组织类器官平台可准确再现BRCA1/2 mut和BRCA WT的前驱组织。这使癌症得以在培养皿中演化，成为机制研究和筛选方法以鉴定新型药物靶点的理想模型。

查看英文原文 English abstract

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.

利益披露 Disclosure

N. Yucer, None.. A. Okimoto, None.. S. Dhungana, None.. D. Bacich, None.. R. Webster, None.. B. German Falcon, None.. M. Jones, None.. S. Parker, None.. B. J. Rimel, None.. L. Ellis, None.. M. Freedman, None.. K. Lawrenson, None.. S. Gayther, None.

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