背景:尽管最近的研究取得了进展,我们对原因的基本理解仍然存在关键的缺陷,发病机制,和许多癌症的自然史,尤其是患者在从恶性表型到侵袭表型的转变过程中对药物和介质的反应的异质性。对癌症发病机理的解释一直受到患者样本获取有限的限制,肿瘤异质性和缺乏可靠的生物学模型。癌症治疗的改善取决于对病因的进一步了解,遗传,生物,肿瘤微环境的临床异质性。患者来源的类器官概括了原发性肿瘤的基本特征,包括组织学复杂性和遗传异质性,这有助于预测患者对药物的反应。
方法:来自健康供体的人iPSCs,乳腺癌和卵巢癌患者成功分化为等基因肝,心脏,神经和内皮谱系。使用从肿瘤组织分离的原代细胞建立多细胞类器官,来自卵巢癌和乳腺癌患者的与肿瘤(NAT)和脂肪组织(间充质干细胞的来源)相邻的组织学正常组织。进一步繁殖这些类器官并用于耐药性/敏感性研究。
结果:卵巢癌和乳腺癌患者的类器官在耐药性和敏感性方面表现出异质性。iPSCs来源的心肌细胞,肝细胞和神经元显示卵巢癌患者化疗药物敏感性的供体间差异,乳腺癌患者和健康捐献者。
结论:我们报告了一种新的综合平台的开发,以促进使用患者的原代细胞的临床决策,iPSC及其衍生物,肿瘤学研究的临床相关模型。
BACKGROUND: Despite recent advances in research, there are still critical lacunae in our basic understanding of the cause, pathogenesis, and natural history of many cancers, especially heterogeneity in patient response to drugs and mediators in the transition from malignant to invasive phenotypes. The explication of the pathogenesis of cancer has been constrained by limited access to patient samples, tumor heterogeneity and lack of reliable biological models. Amelioration in cancer treatment depends on further understanding of the etiologic, genetic, biological, and clinical heterogeneity of tumor microenvironment. Patient-derived organoids recapitulate the basic features of primary tumors, including histological complexity and genetic heterogeneity, which is instrumental in predicting patient response to drugs.
METHODS: Human iPSCs from healthy donors, breast and ovarian cancer patients were successfully differentiated towards isogenic hepatic, cardiac, neural and endothelial lineages. Multicellular organoids were established using Primary cells isolated from tumor tissues, histologically normal tissues adjacent to the tumors (NATs) and adipose tissues (source of Mesenchymal Stem Cells) from ovarian and breast cancer patients. Further these organoids were propagated and used for drug resistance/sensitivity studies.
RESULTS: Ovarian and breast cancer patients\' organoids showed heterogeneity in drug resistance and sensitivity. iPSCs-derived cardiomyocytes, hepatocytes and neurons showed donor-to-donor variability of chemotherapeutic drug sensitivity in ovarian cancer patients, breast cancer patients and healthy donors.
CONCLUSIONS: We report development of a novel integrated platform to facilitate clinical decision-making using the patient\'s primary cells, iPSCs and derivatives, to clinically relevant models for oncology research.