TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells

Abstract

Liver metastasis is a leading cause of death in patients with colorectal cancer. We previously found that colorectal cancer tumor-initiating cells (TICs) expressing CD110, the thrombopoietin (TPO)-binding receptor, mediate liver metastasis. Here, we show that TPO promotes metastasis of CD110+ TICs to the liver by activating lysine degradation. Lysine catabolism generates acetyl-CoA, which is used in p300-dependent LRP6 acetylation. This triggers tyrosine phosphorylation of LRP6, ultimately activating Wnt signaling to promote self-renewal of CD110+ TICs. Lysine catabolism also generates glutamate, which modulates the redox status of CD110+ TICs to promote liver colonization and drug resistance. Mechanistically, TPO-mediated induction of c-myc orchestrates recruitment of chromatin modifiers to regulate metabolic gene expression. Our findings, therefore, establish TPO as a component of the physiological environment critical for metastasis of colorectal cancer to the liver.