Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Commun. 2017 Apr 7;8:14922. doi: 10.1038/ncomms14922.
Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
腺鳞肺癌预后极差，可能源于细胞可塑性。在这里，我们通过在自发和移植模型中敲除 Lkb1（Stk11），证实了 KRAS+肺腺癌（ADC）向鳞状细胞癌（SCC）的谱系转换。染色质分析显示，在包括 Sox2、ΔNp63 和 Ngfr 在内的鳞状谱系基因中，H3K27me3 的丢失和 H3K27ac 和 H3K4me3 的获得。与 ADC 病变相比，SCC 病变中 H3K27 甲基转移酶 EZH2 的水平更高，但 SCC 病变中明显缺乏必需的多梳抑制复合物 2（PRC2）亚基 EED。在人类肺 SCC 和 ADSCC 肿瘤中的 SCC 区域中，也存在高 EZH2 但 H3K27me3 标记明显缺乏的模式。通过 FACS 分离的细胞群，我们证明了支气管肺泡干细胞和 club 细胞是 SCC 转化肿瘤的可能起源细胞。这些发现揭示了谱系特异性肺癌的表观遗传学和细胞起源。
