Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer.
Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer.
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DOI：
10.1186/s13046-023-02689-y
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发表时间：
2023-05-04
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p16启动子甲基化导致表观遗传基因沉默——被称为p16表观突变——在人类结直肠癌中经常发现，在衰老个体的正常结肠粘膜中也很常见。因此，为了改善结直肠癌（CRC）患者的临床护理，我们探讨了年龄相关的p16上皮化在肠道肿瘤发生中的作用。我们建立了一个小鼠模型，该模型复制了在人类crc中观察到的两种常见遗传和表观遗传事件：Apc突变和p16增殖。我们对肿瘤的发展和进展进行了长期生存和组织学分析。收集小鼠结肠上皮细胞和肿瘤，采用RNA测序（RNA-seq）、定量PCR和流式细胞术分析。我们进行了单细胞RNA测序（scRNA-seq）来表征肿瘤进展过程中肿瘤浸润性免疫细胞的特征。我们测试了抗pd - l1免疫治疗是否会影响荷瘤小鼠的总体生存，以及抑制表观遗传调控和免疫检查点是否更有效。与仅携带Apc突变的小鼠相比，携带Apc突变和p16突变的小鼠的生存期明显缩短，肿瘤生长明显增加。有趣的是，p16上皮化的结肠肿瘤表现出干扰素通路激活，程序性死亡配体1 （Pdl1）表达增加，免疫细胞浸润增强。scRNA-seq进一步揭示了Foxp3+ Tregs和γδT17细胞的存在，它们有助于免疫抑制肿瘤微环境（TME）。此外，我们表明，使用DNA甲基化抑制剂和PD-L1免疫检查点抑制剂的联合治疗比单独阻断任何一种途径更有效地改善荷瘤小鼠的生存。我们的研究表明，年龄依赖性p16上皮化为息肉向结肠癌的恶性转化创造了一个允许的微环境。我们的研究结果为未来p16坏死患者的靶向治疗提供了机制基础。在线版本包含补充材料，可在10.1186/s13046-023-02689-y获得。
Methylation of the p16 promoter resulting in epigenetic gene silencing—known as p16 epimutation—is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis. We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA sequencing (RNA-seq), quantitative PCR, and flow cytometry. We performed single-cell RNA sequencing (scRNA-seq) to characterize tumor-infiltrating immune cells throughout tumor progression. We tested whether anti-PD-L1 immunotherapy affects overall survival of tumor-bearing mice and whether inhibition of both epigenetic regulation and immune checkpoint is more efficacious. Mice carrying combined Apc mutation and p16 epimutation had significantly shortened survival and increased tumor growth compared to those with Apc mutation only. Intriguingly, colon tumors with p16 epimutation exhibited an activated interferon pathway, increased expression of programmed death-ligand 1 (Pdl1), and enhanced infiltration of immune cells. scRNA-seq further revealed the presence of Foxp3+ Tregs and γδT17 cells, which contribute to an immunosuppressive tumor microenvironment (TME). Furthermore, we showed that a combined therapy using an inhibitor of DNA methylation and a PD-L1 immune checkpoint inhibitor is more effective for improving survival in tumor-bearing mice than blockade of either pathway alone. Our study demonstrated that age-dependent p16 epimutation creates a permissive microenvironment for malignant transformation of polyps to colon cancer. Our findings provide a mechanistic rationale for future targeted therapy in patients with p16 epimutation. The online version contains supplementary material available at 10.1186/s13046-023-02689-y.
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DOI：
10.1038/nrclinonc.2013.42
发表时间：
2013-05
期刊：
Nature reviews. Clinical oncology
影响因子：
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通讯作者：
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影响因子：
11.2
作者：
Belinsky SA;Grimes MJ;Picchi MA;Mitchell HD;Stidley CA;Tesfaigzi Y;Channell MM;Liu Y;Casero RA Jr;Baylin SB;Reed MD;Tellez CS;March TH
通讯作者：
March TH
影响因子：
18.2
作者：
Campisi J
通讯作者：
Campisi J
影响因子：
6
作者：
Chan, AOO;Issa, JPJ;Rashid, A
通讯作者：
Rashid, A
DOI：
10.1088/1742-5468/2008/10/p10008
发表时间：
2008-10-01
影响因子：
2.4
作者：
Blondel, Vincent D.;Guillaume, Jean-Loup;Lefebvre, Etienne
通讯作者：
Lefebvre, Etienne