A study from Dr. Monga’s group in Hepatology identifies subset of hepatocellular cancers that show simultaneous activation of Wnt and Nrf2 signaling. Other PLRC members who contributed to the study include 2020 P&F recipient Dr. Akshata Moghe; Directors of CBRPC Dr. Aatur Singhi and Dr. David Geller; Assistant Director and Manager of GSBC Dr. Silvia Liu; and Associate Members (Drs. Junyan Tao, Aaron Bell, Michael Oertel).
Tao J, Krutsenko Y, Moghe A, Singh S, Poddar M, Bell A, Oertel M, Singhi AD, Geller D, Chen X, Lujambio A, Liu S, Monga SP. Nrf2 and β-catenin coactivation in hepatocellular cancer: Biological and therapeutic implications. Hepatology. 2021 Feb 2. doi: 10.1002/hep.31730. Epub ahead of print. PMID: 33529367.
Background: Hepatocellular cancer (HCC) remains a major unmet clinical need. Although activating CTNNB1 mutations are seen in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Co-expression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between β-catenin and Nrf2 signaling in HCC.
Methods: Public HCC datasets were assessed for concomitant presence of CTNNB1 mutations and either mutations in NFE2L2 or KEAP1, or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following co-expression of T41A-CTNNB1 with either WT-, G31A- or T80K-NFE2L2. Based on mTORC1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mTOR inhibitor was investigated.
Results: Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were due to mutations in NFE2L2/KEAP1. Co-expression of mutated-CTNNB1 with mutant-NFE2L2 but not WT-NFE2L2 led to HCC development and mortality by 12-14 weeks. These HCCs were positive for β-catenin targets like Glutamine synthetase and Cyclin-D1, and Nrf2 targets like NAD(P)H Quinone Dehydrogenase 1 and peroxiredoxin 1. RNA-seq and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (Iron Homeostasis and Glioblastoma Multiforme signaling) and expected (Glutamine Metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5mg/kg diet ad libitum), which led to >50% decrease in tumor burden. Conclusion Co-activation of β-catenin and Nrf2 is evident in 9% of all human HCCs. Co-expression of mutant-NFE2L2 and mutant-CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.
Keywords: CTNNB1; Glutamine synthetase; KEAP1; NFE2L2; Wnt pathway; liver tumors; mTOR inhibitor; mutations.