PO.ET01.03 · 实验与分子治疗
FGF19/FGFR4轴:结直肠癌肿瘤发生和治疗耐药的关键驱动因素
FGF19/ FGFR4 Axis: A key driver in tumorigenesis and treatment resistance in colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
结直肠癌(CRC)仍然是治疗耐药性最强的恶性肿瘤之一,但其耐药机制尚未完全阐明。我们的目的是明确这些机制并鉴定新的治疗靶点,以改善治疗结局。我们研究了成纤维细胞生长因子(FGF)信号传导,特别是FGF19/FGF受体(FGFR)4轴,在CRC肿瘤生长和治疗反应中的作用。该轴之所以引人注目,是因为我们的初步数据显示:(i)基于公开可用的单细胞RNA-seq和我们配对患者标本的bulk RNA-seq,FGF19和FGFR4在人CRC中共同过表达;(ii)在TCGA-COAD队列中,FGF19过表达与更差的无复发生存期(RFS)相关;以及(iii)FGF19和FGFR4的表达均与不良的总生存期(OS)相关。重要的是,FGF19/FGFR4信号传导是MAPK和WNT/beta-catenin通路的上游调控因子,而这些通路是CRC肿瘤发生和治疗耐药的关键驱动因素。我们假设FGF19/FGFR4轴的自激活促进CRC的肿瘤生长、存活和治疗耐药。为剖析该轴的功能贡献,CRC细胞系接受选择性FGFR4抑制或诱导FGF19过表达。使用成熟的体外实验评估对活力、增殖、克隆形成生长、侵袭和药物敏感性的影响,同时通过qRT-PCR和Western blotting检查机制变化。在功能上,使用选择性抑制剂BLU9931靶向FGFR4影响了所有关键的癌症标志:凋亡增加、增殖减少、克隆形成能力受抑制以及侵袭减弱。用BLU9931预处理使细胞对标准化疗药物5-氟尿嘧啶(5-FU)敏感,协同增强了细胞毒性。相反,FGF19过表达激活ERK1/2和beta-catenin信号传导以促进增殖,通过将细胞维持在G1保护期诱导对5-FU的耐药,并促进化疗后的快速恢复。我们的研究结果支持这一假设,即FGF19-FGFR4轴是CRC进展和治疗耐药的关键驱动因素,强调了开发针对这一肿瘤特异性信号轴的靶向疗法的合理性。
查看英文原文 English abstract
Colorectal cancer (CRC) remains one of the most treatment-resistant malignancies, yet the mechanisms underlying this resistance are not fully understood. Our GOAL is to define these mechanisms and identify new therapeutic targets to improve treatment outcomes. We investigate the role of the Fibroblast Growth Factor (FGF) signaling, particularly the FGF19/FGF Receptor (FGFR) 4 axis, in CRC tumor growth and therapeutic response. This axis is compelling because our preliminary data show that: (i) FGF19 and FGFR4 are co-overexpressed in human CRC, based on publicly available single-cell RNA-seq and bulk RNA-seq of our paired patient specimens; (ii) FGF19 overexpression correlates with worse relapse-free survival (RFS) in the TCGA-COAD cohort; and (iii) both FGF19 and FGFR4 expression correlate with poor overall survival (OS). Importantly, FGF19/FGFR4 signaling is an upstream regulator of the MAPK and WNT/beta-catenin pathways, key drivers of tumorigenesis and treatment resistance in CRC. We HYPOTHESIZE that autoactivation of the FGF19/FGFR4 axis promotes tumor growth, survival, and treatment resistance in CRC. To dissect this axis's functional contributions, CRC cell lines underwent selective FGFR4 inhibition or induced FGF19 overexpression. Effects on viability, proliferation, clonogenic growth, invasion, and drug sensitivity were assessed using established in vitro assays, while mechanistic changes were examined by qRT-PCR and Western blotting. Functionally, targeting FGFR4 with the selective inhibitor BLU9931 impacted all critical cancer hallmarks: increased apoptosis, reduced proliferation, suppressed clonogenic capacity, and diminished invasion. Pre-treatment with BLU9931 sensitized cells to 5-fluorouracil (5-FU), a standard chemotherapeutic agent, enhancing cytotoxicity synergistically. Conversely, FGF19 overexpression activated ERK1/2 and beta-catenin signaling to promote proliferation, induced resistance to 5-FU by maintaining cells in the G1-protective phase, and facilitated rapid post-chemotherapy recovery. Our findings support the hypothesis that the FGF19-FGFR4 axis is a key driver of CRC progression and therapy resistance, underscoring the rationale for developing targeted therapies against this tumor-specific signaling axis.
利益披露 Disclosure
A. Nguyen, None..
B. M. Boman, None.