Notch signaling promotes liver carcinogenesis becoming an appealing target for new therapies

Less than 30% of newly diagnosed hepatocellular carcinoma (HCC) patients are eligible for curative therapies such as resection, liver transplantation, or local ablation. Hence, there is an increasing need to develop new drugs for a disease that, besides being the third leading cause of cancer death worldwide, has tripled its incidence in the last decades in the United States. An article published in Gastroenterology by the IDIBAPS Translational Research in Hepatic Oncology group, led by the ICREA investigator Prof Josep Maria Llovet, demonstrates that Notch signaling is activated in a subset of human HCC samples, and promotes liver tumor formation in genetically engineered mice. In addition, the study reports a Notch gene signature able to predict response to Notch inhibition in experimental models of liver cancer. First authorship of the manuscript is shared by Dr Augusto Villanueva and Clara Alsinet . The study is the result of an international collaboration that includes renown leaders in the field from the University of Pennsylvania (Philadelphia), the Broad Institute and Dana-Farber Cancer Institute at Harvard Medical School (Boston), and Mount Sinai School of Medicine (New York).

Notch cascade is a complex and highly evolutionary conserved signalling pathway. It was originally discovered as critical regulator of cell fate and development in several tissues. Recently, numerous studies have suggested a potential role of Notch signaling de-regulation in carcinogenesis. Its activation in diseases such as leukemia and solid tumors like lung cancer is well established, but evidence of its role in HCC was limited and ambiguous in terms of antitumoral effects following its inhibition. The work led by IDIBAPS’ investigators is the first comprehensive and integrative approach to explore the role of Notch signaling in liver cancer pathogenesis.

The study shows how activation of Notch signaling promotes liver carcinogenesis in a genetically engineered mouse model. Through comparative functional genomic analysis, investigators generated a Notch gene signature and found Notch activation in approximately one third of the 683 human HCC samples analysed. Finally, the article incorporates experimental evidence on how Notch inhibition reduces cell proliferation in liver cancer cell lines with the Notch signature. Overall, the investigation introduces Notch as an appealing target in a subset of HCC patients for new drug development initiatives, and provides a genomic biomarker to identify the candidate best responders. . The IDIBAPS group that led the study will keep on working in this research line within initiatives such as the International Liver Cancer Association (ILCA) or HEPTROMIC, an FP-7 funded research consortium coordinated from IDIBAPS by Prof. Josep Maria Llovet.

Article reference: Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, Rodriguez-Carunchio L, Solé M, Thung S, Stanger BZ, Llovet JM. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012 Dec;143(6):1660-1669.e7. doi: 10.1053/j.gastro.2012.09.002. Epub 2012 Sep 11.

Comment in: Strazzabosco M, Fabris L. Notch signaling in hepatocellular carcinoma: guilty in association! Gastroenterology. 2012 Dec;143(6):1430-4. doi: 10.1053/j.gastro.2012.10.025. Epub 2012 Oct 22.