PO.TB09.02 · 肿瘤生物学

EED在肺癌组织学转化中驱动小细胞肺癌神经内分泌表型

EED drives the small cell lung cancer neuroendocrine phenotype in lung cancer histological transformation

编号 3528 展板 4 时间 4/20 02:00–05:00 区域 Section 33 主讲 Yixiang Li, MS;PhD

分会场 Tumor Evolution

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作者与单位 Authors & Affiliations

Yixiang Li¹, Yasmin N. Laimon², Hyeonseo Cho¹, Marina Vivero², Gabriel R. De Oliveira², Andrew Delcea², Varunika Savla², Yuting Chen³, Yavuz Durmaz¹, Xintao Qiu¹, Shweta Kukreja¹, Rong Li¹, Talal El Zarif⁴, Wesley S. Lu¹, McKayla Van Orden¹, Jacob E Berchuck⁵, Roderick Bronson⁶, Shuqiang Li⁷, Hongbin Ji³, Katerina A. Politi⁸, Matthew L. Freedman¹, Henry Long¹, Sabina Signoretti², Matthew Gilbert Oser¹

¹DFCI/Harvard Medical School, Boston, MA,²Department of Pathology, Brigham and Women’s Hospital, Boston, MA,³Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China,⁴Dana-Farber Cancer Institute, Boston, MA,⁵Winship Cancer Institute/Emory University School of Medicine, Atlanta, GA,⁶Harvard Medical School, Boston, MA,⁷Broad Institute of MIT and Harvard, Cambridge, MA,⁸Yale Cancer Center, New Haven, CT

摘要 Abstract

中文摘要

从肺腺癌（LUAD）向小细胞肺癌（SCLC）的肺癌组织学转化可作为对靶向治疗的一种耐药机制而发生，尤其是在同时携带RB1和TP53突变的EGFR突变LUAD中。SCLC转化预后差，且没有靶向治疗可阻断SCLC转化。PRC2复合物表达增加与SCLC转化相关，但PRC2复合物在功能上对SCLC转化是否必需尚不清楚。在本研究中，我们利用两个最先进的基于CRISPR的、自体免疫功能健全的基因工程小鼠模型（GEMM），结合全面的基因组、转录组和表观基因组分析，研究了PRC2复合物的支架组分EED在SCLC肿瘤发生以及LUAD向SCLC转化中的功能作用。在一个从头（de novo）SCLC GEMM中，我们表明EED的缺失阻碍SCLC发育，并通过一个NEUROD1阳性的中间细胞状态选择性地促进LUAD的形成。从机制上讲，EED缺失去抑制了由H3K27me3和H3K4me3共同标记的二价基因，包括LUAD致癌性RAS、PI3K和MAPK通路基因，从而促进向LUAD的转化。与此一致，这些相同的信号通路基因在人类SCLC患者来源异种移植中被二价标记并沉默，表明存在一种保守的PRC2介导机制来抑制LUAD致癌信号，以维持SCLC的神经内分泌身份。在一个新的基于CRISPR的、伴RB1/TP53缺失的EGFR突变LUAD GEMM中，我们发现EED对于EGFR撤除后LUAD向SCLC的转化及转移进展是必需的。总之，这些发现将PRC2复合物确定为一种维持SCLC神经内分泌身份的表观遗传调控因子，并强调了EED抑制作为一种预防高危LUAD发生SCLC转化的潜在治疗方法。

查看英文原文 English abstract

Lung cancer histological transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) can occur as a resistance mechanism to targeted therapies, particularly in EGFR -mutant LUADs with concurrent RB1 and TP53 mutations. SCLC transformation has a poor prognosis and there are no targeted therapies to block SCLC transformation. Increased PRC2 complex expression is correlated with SCLC transformation, but it is unknown whether PRC2 complex is functionally necessary for SCLC transformation. In this study, we investigated the functional role of EED, a scaffolding component of the PRC2 complex, in SCLC tumorigenesis and in LUAD to SCLC transformation utilizing two state-of-the-art CRISPR-based, autochthonous immunocompetent genetically engineered mouse models (GEMMs) with comprehensive genomic, transcriptomic, and epigenomic analyses. In a de novo SCLC GEMM, we show that loss of EED hinders SCLC development and selects for the formation of LUAD through a NEUROD1-positive intermediate cell state. Mechanistically, EED loss de-represses bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes, to promote transformation to LUAD. Consistently, these same signaling pathway genes are bivalently marked and silenced in human SCLC patient-derived xenografts, indicating a conserved PRC2-mediated mechanism to repress LUAD oncogenic signaling to maintain the SCLC neuroendocrine identity. In a novel CRISPR-based EGFR -mutant LUAD GEMM with RB1/TP53 loss, we found EED is necessary for LUAD to SCLC transformation and metastatic progression following EGFR withdrawal. Altogether, these findings identify the PRC2 complex as an epigenetic regulator that maintains the SCLC neuroendocrine identity and highlights EED inhibition as a potential therapeutic approach to prevent SCLC transformation in high-risk LUAD.

利益披露 Disclosure

Y. Li, None.. Y. N. Laimon, None.. H. Cho, None.. M. Vivero, None.. G. R. De Oliveira, None.. A. Delcea, None.. V. Savla, None.. Y. Chen, None.. Y. Durmaz, None.. X. Qiu, None.. S. Kukreja, None.. R. Li, None.. T. El Zarif, None.. W. S. Lu, None.. M. Van Orden, None.. J. Berchuck, None.. R. Bronson, None.. S. Li, None.. H. Ji, None. K. A. Politi, AstraZeneca ). Roche/Genentech ). Boehringer Ingelheim ). D2G Oncology ). MSKCC/MolecularMD Patent. M. L. Freedman, Precede Biosciences ). H. Long, None.. S. Signoretti, None. M. G. Oser, Novartis ). Circle Pharma ). Amgen ). Auron Therapeutics ). Eli Lilly ). Takeda ). BMS ).

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