PO.MCB07.01 · 分子与细胞生物学

HMGA1：通过诱导FGF19信号驱动结肠癌变的表观遗传驱动因素，可通过FGFR4受体阻断进行靶向治疗

HMGA1: An epigenetic driver of colon carcinogenesis by inducing FGF19 signals which can be targeted with FGFR4 receptor blockade

编号 4752 展板 2 时间 4/21 09:00–12:00 区域 Section 24 主讲 Yuze Du, BS

分会场 Oncogenic Transcription Factors and Cancer Programs

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作者与单位 Authors & Affiliations

Yuze Du¹, Li Luo², Jung-Hyun Kim³, Bailey West⁴, Tatianna Larman⁵, Leslie Cope⁶, Eric R. Fearon⁷, Cynthia Sears⁸, Linda Resar⁹

¹Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD,²Johns Hopkins University School of Medicine, Baltimore, MD,³Research Institute, National Cancer Center, Goyang-si, Gyeonggido, Korea, Republic of,⁴Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD,⁵Pat Gastrointestinal Liver Pathology, Johns Hopkins University School of Medicine, Baltimore, MD,⁶Onc Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, MD,⁷Oncology, University of Michigan, Ann Arbor, MI,⁸DOM Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, MD,⁹Hematology, Johns Hopkins University School of Medicine, Baltimore, MD

摘要 Abstract

中文摘要

晚期结直肠癌（CRC）仍是重大的医疗负担，且在较年轻患者中发病率不断上升，亟需开发新型靶向疗法。编码高迁移率族A1（HMGA1）染色质调节因子的基因在成体干细胞（包括结肠干细胞）以及多种肿瘤中富集，其高水平表达预示着不良临床结局。事实上，与非恶性结肠上皮相比，HMGA1是CRC中过表达程度最高的基因之一。为定义HMGA1在结肠癌变中可靶向的潜在机制，我们在临床前模型和人类肿瘤中进行了基因表达研究（bulk、单细胞RNA测序）和染色质可及性检测（ATACseq），揭示了FGF19生长因子是HMGA1在CRC中的下游效应分子。我们此前已发现，在胰腺癌KPC小鼠模型和人类原位异种移植中，使用针对FGFR4受体的临床抑制剂（BLU9931）阻断FGF19信号可减少胰腺肿瘤和间质形成，同时延长生存期。在肠上皮细胞携带腺瘤性结肠息肉病（ApcMin）失活的小鼠中，我们发现在接种产肠毒素脆弱拟杆菌（ETBF，一种在CRC患者中常见的致癌细菌）后Hmga1被诱导。在该模型中，ETBF接种导致强健的远端结肠肿瘤发生和HMGA1依赖性的Wnt信号放大。HMGA1还激活小鼠FGF19（Fgf15）的表达。引人注目的是，在人类CRC肿瘤中，HMGA1和FGF19同样上调并呈正相关（r=0.71，P<0.00001；TCGA）。此外，在人类CRC细胞系（SW620）中沉默HMGA1可抑制FGF19表达。通过对Apc失活的小鼠结肠隐窝细胞进行ATACseq，HMGA1增强了小鼠Fgf15位点的染色质可及性（P<0.001），提示HMGA1打开染色质以激活Fgf15表达。因此，我们通过用BLU9931处理人类CRC细胞（SW620），检验了FGFR4抑制在CRC中是否具有抗肿瘤疗效。FGFR4阻断以剂量依赖方式破坏克隆形成能力，重现了HMGA1沉默的效应。总之，这些数据阐明了HMGA1-FGF19轴是驱动结肠癌变的一条新型表观遗传通路，也是一个有前景的治疗靶点。

查看英文原文 English abstract

Advanced colorectal cancer (CRC) continues to be a significant healthcare burden with increasing incidence in younger patients, necessitating the development of novel targeted therapies. The gene encoding the High Mobility Group A1 (HMGA1) chromatin regulator is enriched in adult stem cells, including colon stem cells, and diverse tumors where high levels portend adverse clinical outcomes. Indeed, HMGA1 is among the genes most highly overexpressed in CRC compared to nonmalignant colon epithelium. To define targetable mechanisms underlying HMGA1 in colon carcinogenesis, we performed gene expression studies (bulk, single cell RNA sequencing) and chromatin accessibility assays (ATACseq) in preclinical models and human tumors which unveiled the FGF19 growth factor as a downstream effector of HMGA1 in CRC. We had previously discovered that disrupting FGF19 signaling with the clinical inhibitor to the FGFR4 receptor (BLU9931) in KPC mouse models of pancreatic cancer and human orthotopic xenografts decreases pancreatic tumor and stroma formation while prolonging survival. In mice with intestinal epithelial cells harboring Adenomatous polyposis coli ( Apc Min ) inactivation, we found that Hmga1 is induced following inoculation with enterotoxigenic Bacteroides fragilis (ETBF), a common oncogenic bacterium in humans with CRC. In this model, ETBF inoculation results in robust distal colon tumorigenesis and HMGA1-dependent amplification of Wnt signaling. HMGA1 also activates murine FGF19 ( Fgf15 ) expression. Strikingly, in human CRC tumors, HMGA1 and FGF19 are also up-regulated and positively correlated (r=0.71, P <0.00001; TCGA). Further, silencing HMGA1 in human CRC cell lines (SW620) represses FGF19 expression. By ATACseq in mouse colon crypt cells with Apc inactivation, HMGA1 enhances chromatin accessibility at the murine Fgf15 locus ( P <0.001), suggesting that HMGA1 opens chromatin to activate Fgf15 expression. We therefore tested whether FGFR4 inhibition has anti-tumor efficacy in CRC by treating human CRC cells (SW620) with BLU9931. FGFR4 blockade disrupts clonogenicity in a dose-dependent fashion, recapitulating effects of HMGA1 silencing. Together, these data illuminate the HMGA1-FGF19 axis as a novel epigenetic pathway driving colon carcinogenesis and a promising therapeutic target.

利益披露 Disclosure

Y. Du, None.. L. Luo, None.. J. Kim, None.. B. West, None.. T. Larman, None.. L. Cope, None.. E. R. Fearon, None.. C. Sears, None. L. Resar, PharmaEssentia Other, LR reports investigator-initiated grant funding administered through her institution from PharmaEssentia for an unrelated project.

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