Introduction
Cancer exhibits high mortality due to lymph node and distant metastasis, which substantially compromises treatment efficacy. Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and lethal cancer with tendency of early lymph node metastasis. However, the molecular mechanisms underlying esophageal cancer metastasis, including the interactions among genome, transcriptome, proteome, and post-translational modifications (PTMs), remain incompletely characterized. Furthermore, recent studies showed that lactate serves as a signaling molecule that can induce lysine lactylation (Kla) [1], a novel type of PTM, which was extensively involved in tumor biological processes [2].
Aims & Methods
Herein, we performed a multi-omics analysis integrating genomic, transcriptomic, proteomic, and lactylome data from 99 samples across 36 metastatic ESCC patients. The interactions among the genome, transcriptome, proteome were comprehensively investigated. Key proteins and Kla sites driving ESCC metastasis were identified from the integrative analysis. Their clinical relevance and prognostic significance were validated by immunohistochemical assay on clinical samples. Furthermore, their biological functions and underlying mechanism in ESCC cell migration and invasion were verified through in-vitro and in-vivo experiments.
Results
We first established the genome, transcriptome, proteome, and lactylome landscape of metastatic ESCC. We identified prognosis-relevant immunity-driving waves in the metastatic cascade, with intercellular adhesion molecule 1 functioning as a critical regulator of invasion and migration both in vitro and in vivo. We demonstrated extensive involvement of lysine Kla in metastasis, primarily through metabolic pathway modulation. The ESCC proteome, modulated by Kla, exhibited comprehensive interactions with genomic and transcriptomic elements through both cis- and trans-regulatory mechanisms. Notably, phosphoglycerate mutase 1 (PGAM1) K251 lactylation promoted metastasis both in vitro and in vivo by enhancing its molecular interaction with actin gamma 1, thereby affecting actin kinetics and cell motility.
Conclusion
We first established the genome, transcriptome, proteome, and lactylome landscape of metastatic ESCC. We identified prognosis-relevant immunity-driving waves in the metastatic cascade, with intercellular adhesion molecule 1 functioning as a critical regulator of invasion and migration both in vitro and in vivo. We demonstrated extensive involvement of lysine Kla in metastasis, primarily through metabolic pathway modulation. The ESCC proteome, modulated by Kla, exhibited comprehensive interactions with genomic and transcriptomic elements through both cis- and trans-regulatory mechanisms. Notably, phosphoglycerate mutase 1 (PGAM1) K251 lactylation promoted metastasis both in vitro and in vivo by enhancing its molecular interaction with actin gamma 1, thereby affecting actin kinetics and cell motility.
References
[1] Zhang, D., Tang, Z., Huang, H., Zhou, G., Cui, C., Weng, Y., Liu, W., Kim, S., Lee, S., Perez-Neut, M., et al. (2019). Metabolic regulation of gene expression by histone lactylation. Nature 574, 575-580. Doi:10.1038/s41586-019-1678-1.
[2] Li H, Sun L, Gao P, Hu H. Lactylation in cancer: Current understanding and challenges. Cancer Cell. 2024 Nov 11;42(11):1803-1807. Doi: 10.1016/j.ccell.2024.09.006. Epub 2024 Oct 10.