Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Program, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
Nat Genet. 2021 Jun;53(6):881-894. doi: 10.1038/s41588-021-00859-2. Epub 2021 May 10.
Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.
食管鳞状细胞癌 (ESCC) 存在反复发生的染色体 3q 扩增，其靶标是转录因子 SOX2。除了在 ESCC 中作为癌基因的作用外，SOX2 还在鳞状食管的发育和成人食管前体细胞的维持中发挥作用。为了比较正常组织和恶性组织中的 Sox2 活性，我们开发了工程化的鼠类食管类器官，涵盖了从正常食管到 Sox2 诱导的鳞状细胞癌，并绘制了 Sox2 结合图谱以及从正常到癌症的表观遗传和转录景观。虽然致癌性 Sox2 很大程度上维持了在正常组织中观察到的作用，但 Sox2 的过表达与 p53 和 p16 的失活一起促进了染色质重塑和 Sox2 顺式作用元件的进化。与 Klf5 一起，致癌性 Sox2 获得了新的结合位点，并增强了 Stat3 等癌基因的活性。此外，致癌性 Sox2 激活内源性逆转录病毒，诱导双链 RNA 的表达，并依赖 RNA 编辑酶 ADAR1。这些数据揭示了 SOX2 在 ESCC 中的功能，确定了可靶向的脆弱性。
