Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) typically develops in cirrhosis, a condition characterized by Hedgehog (Hh) pathway activation and accumulation of Hh-responsive myofibroblasts. Although Hh signaling generally regulates stromal-epithelial interactions that support epithelial viability, the role of Hh-dependent myofibroblasts in hepatocarcinogenesis is unknown. Here, we used human HCC samples, a mouse HCC model, and hepatoma cell/myofibroblast cocultures to examine the hypothesis that Hh signaling modulates myofibroblasts' metabolism to generate fuels for neighboring malignant hepatocytes. The results identify a novel paracrine mechanism whereby malignant hepatocytes produce Hh ligands to stimulate glycolysis in neighboring myofibroblasts, resulting in release of myofibroblast-derived lactate that the malignant hepatocytes use as an energy source. This discovery reveals new diagnostic and therapeutic targets that might be exploited to improve the outcomes of cirrhotic patients with HCCs.
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Isaac S
IS
Chan
Cynthia D
CD
Guy
Yuping
Y
Chen
Jiuyi
J
Lu
Marzena
M
Swiderska-Syn
Gregory A
GA
Michelotti
Gamze
G
Karaca
Guanhua
G
Xie
Leandi
L
Krüger
Wing-Kin
WK
Syn
Blair R
BR
Anderson
Thiago A
TA
Pereira
Steve S
SS
Choi
Albert S
AS
Baldwin
Anna Mae
AM
Diehl
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000502:physiology; D053823:Hedgehog Proteins / Q000378:metabolism / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D050155:Lipogenesis / Q000502:physiology; D008113:Liver Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D019899:Paracrine Communication / Q000502:physiology*
D053823:Hedgehog Proteins; D019344:Lactic Acid