Curiel-Garcia Alvaro, Holmstrom Sam R, Castillo Cristina, Palermo Carmine F, Sastra Steven A, Andren Anthony, Tomassoni Lorenzo, Zhang Li, Le Large Tessa Y S, Sagalovskiy Irina, Ross Daniel R, Wong Winston, Shaw Kaitlin, Genkinger Jeanine, Hibshoosh Hanina, Manji Gulam A, Iuga Alina C, Schmid Roland M, Johnson Kristen, Badgley Michael A, Laise Pasquale, Lyssiotis Costas A, Shah Yatrik M, Califano Andrea, Maurer H Carlo, Olive Kenneth P
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY.
Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY.
bioRxiv. 2025 Jun 10:2023.03.19.533333. doi: 10.1101/2023.03.19.533333.
KRAS is the archetypal oncogenic driver of pancreatic cancer. To identify new modulators of KRAS activity in human pancreatic ductal adenocarcinoma (PDAC), we performed regulatory network analysis on a large collection of expression profiles from laser capture microdissected samples of PDAC and benign controls. We discovered that BMAL2, a member of the PAS family of transcription factors, promotes tumor initiation, progression, and post-resection survival, and is highly correlated with KRAS activity. Functional analysis of BMAL2 target genes suggested a role in regulating the hypoxia response, a hallmark of PDAC. Knockout of in multiple human PDAC cell lines reduced cancer cell viability, invasion, and glycolysis, leading to broad dysregulation of cellular metabolism, particularly under hypoxic conditions. We find that BMAL2 directly regulates hypoxia-responsive target genes and is necessary for the stabilization of HIF1A under low oxygen conditions, while simultaneously destabilizing HIF2A. Notably, xenograft studies demonstrated that BMAL2 loss significantly impairs tumor growth and reduces tumor volume, underscoring its functional importance in tumor progression. We conclude that BMAL2 is a master transcriptional regulator of hypoxia responses in PDAC that works downstream of KRAS signaling, possibly serving as a long-sought molecular switch that distinguishes HIF1A- and HIF2A-dependent modes of hypoxic metabolism.
KRAS是胰腺癌典型的致癌驱动因子。为了在人胰腺导管腺癌（PDAC）中鉴定KRAS活性的新调节因子，我们对来自PDAC激光捕获显微切割样本和良性对照的大量表达谱进行了调控网络分析。我们发现，转录因子PAS家族成员BMAL2促进肿瘤起始、进展和切除后存活，并且与KRAS活性高度相关。对BMAL2靶基因的功能分析表明其在调节缺氧反应中起作用，缺氧反应是PDAC的一个特征。在多种人PDAC细胞系中敲除BMAL2可降低癌细胞活力、侵袭和糖酵解，导致细胞代谢广泛失调，尤其是在缺氧条件下。我们发现BMAL2直接调节缺氧反应靶基因，并且在低氧条件下对HIF1A的稳定是必需的，同时使HIF2A不稳定。值得注意的是，异种移植研究表明BMAL2缺失显著损害肿瘤生长并减小肿瘤体积，强调了其在肿瘤进展中的功能重要性。我们得出结论，BMAL2是PDAC中缺氧反应的主要转录调节因子，在KRAS信号下游起作用，可能作为一个长期寻找的分子开关，区分HIF1A和HIF2A依赖的缺氧代谢模式。
