title: Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19.
abstract: Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer.
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Van
authors.initials: V
authors.lastname: Phung
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Darrin A
authors.initials: DA
authors.lastname: Lindhout
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Mondal
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Jer-Yuan
authors.initials: JY
authors.lastname: Hsu
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Humphrey
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Xunshan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Taruna
authors.initials: T
authors.lastname: Arora
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: R Marc
authors.initials: RM
authors.lastname: Learned
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Alex M
authors.initials: AM
authors.lastname: DePaoli
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: Authors' Affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, California lling@ngmbio.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Ling
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D011485:Protein Binding; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; C117476:FGF19 protein, human; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4