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00925njm 22002777a 4500 dc Tummala, Krishna S author Brandt, Marta author Teijeiro, Ana author Graña Castro, Osvaldo author Schwabe, Robert F author Perna, Cristian author Djouder, Nabil author 2017-04-19 Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer. However, its origin remains a debated question. Using human data and various hepatocarcinogenesis mouse models, we show that, in early stages, transformed hepatocytes, independent of their proliferation status, activate hepatic progenitor cell (HPC) expansion. Genetic lineage tracing of HPCs and hepatocytes reveals that, in all models, HCC originates from hepatocytes. However, whereas in various models tumors do not emanate from HPCs, tracking of progenitors in a model mimicking human hepatocarcinogenesis indicates that HPCs can generate benign lesions (regenerative nodules and adenomas) and aggressive HCCs. Mechanistically, galectin-3 and α-ketoglutarate paracrine signals emanating from oncogene-expressing hepatocytes instruct HPCs toward HCCs. α-Ketoglutarate preserves an HPC undifferentiated state, and galectin-3 maintains HPC stemness, expansion, and aggressiveness. Pharmacological or genetic blockage of galectin-3 reduces HCC, and its expression in human HCC correlates with poor survival. Our findings may have clinical implications for liver regeneration and HCC therapy. Cell Rep. 2017;19(3):584-600. 10.1016/j.celrep.2017.03.059 2211-1247 22111247 Cell reports 28423321 http://hdl.handle.net/20.500.12105/7231 DNA damage HCC NAD(+) Adenomas Galectin-3 Hepatic progenitor cells Hepatocytes Lineage tracking Regenerative nodules α-ketoglutarate Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells