title: 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.
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: ZhengMing
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Anus and Intestine Surgery, PLA Central Hospital 150, Luoyang, Henan 471031, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: WenChao
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: YuTing
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: ZhiQian
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: ZhenYu
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anus and Intestine Surgery, PLA Central Hospital 150, Luoyang, Henan 471031, China.
authors.forename: ChunFang
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Traditional Chinese Medicine, Shanghai Cancer Hospital, Fudan University, Shanghai 200032, China.
authors.forename: XiaoYan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: 061101040@fudan.edu.cn.
authors.forename: QingQuan
authors.initials: Q
authors.lastname: Li
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D015179:Colorectal Neoplasms / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D016259:Genes, myc; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D018384:Oxidative Stress; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D013926:Thrombopoietin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D000105:Acetyl Coenzyme A; D013926:Thrombopoietin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D008239:Lysine