结直肠癌（CRC）是世界范围内的一种常见癌症，其发病率每年都在增加。癌症干细胞（CSC）在结直肠癌的发生、发展、复发和转移中发挥着重要作用。调节结直肠癌干细胞发育的分子机制仍不清楚。通过体细胞重编程发现的人类诱导多能干细胞（hiPSC）彻底改变了干细胞生物学和转化医学领域。在本研究中，我们通过使用来自 CRC 细胞的条件培养基 (CM) 进行培养，将 hiPSC 转化为癌症干样细胞。这些转化细胞被称为 hiPSC-CSC，表现出癌症干细胞样特性，包括球状形态以及多能性和 CSC 标记的表达。 HiPSC-CSC 在小鼠模型中显示出致瘤和转移能力。在 hiPSC-CSC 中观察到上皮-间质转化表型，这促进了它们的迁移和血管生成。有趣的是，在 hiPSC-CSC 分化过程中观察到 C-MYC 上调。从机制上讲，CREB结合蛋白（CBP）与C-MYC启动子结合，而组蛋白脱乙酰酶1和3（HDAC1/3）与启动子解离，最终导致分化过程中组蛋白乙酰化和C-MYC转录激活增加。 hiPSC-CSC。使用 CBP 抑制剂进行药物治疗或使用基于 CRISPR/Cas9 的策略消除 CBP 表达可降低 hiPSC-CSC 的干性。这项研究首次证明结直肠 CSC 可以由 hiPSC 产生。通过组蛋白乙酰化上调 C-MYC 在转化过程中起着至关重要的作用。抑制 CBP 是减弱结直肠 CSC 干性的潜在策略。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.