Study of the dialogue between the UPR response and the inflammasome in hepatocellular carcinoma
The most common form of primary liver cancer, hepatocellular carcinoma (HCC) will be the 3rd leading cause of cancer deaths by 2020. Over 80% of HCC cases occur in the context of chronic liver disease. With the rising incidence of obesity, the high prevalence of non-alcoholic fatty liver disease (MAFLD) worldwide, diabetes and an aging population, HCC is the fastest-growing cause of cancer-related mortality.
HCC poses a real clinical challenge, with 80% of HCC patients diagnosed at a late stage with limited treatment options. Sorafenib, a multi-kinase inhibitor, has a modest effect on patient survival, with considerable side effects. Recently, immunotherapy has shown promising but limited results. Improving our understanding of the molecular mechanisms of HCC is vital in order to select new therapeutic targets for improved treatment.
The various risk factors for HCC (steatohepatitis, chronic alcohol consumption, viral hepatitis and diabetes) modify liver cell homeostasis, leading to "endoplasmic reticulum (ER) stress". This ER stress initiates an evolutionarily conserved intracellular response known as the Unreformed Protein Response (UPR). This UPR response is governed by three transmembrane proteins localized in the ER: IRE1, PERK and ATF6. UPR appears to be a key player in the malignant transformation of the liver, underpinning the main features of HCC. UPR markers have also been reported in precancerous stages preceding HCC, notably MASH. Previously, the team highlighted a dialogue between UPR pathways and the inflammasome in the steatosis-MASH transition.
In this thesis, we hypothesized that UPR pathways, particularly IRE1a and its dialogue with the inflammasome, may play a crucial role in HCC.
The aim of this thesis was therefore to investigate this potential dialogue between the UPR, IRE1α and inflammasome pathways in HCC. First, we demonstrated constitutive mobilization of IRE1α endoribonuclease (RNase) activity within biopsies from HCC patients and four human HCC tumor lines.
Using gain- and loss-of-function approaches (pharmacological inhibitors, gene inhibition by RNA silencing and XBP1 over-expression), transcriptomic (RNAseq) and biochemical approaches, and electron microscopy analyses, carried out jointly in human HCC lines and two pre-clinical mouse models of HCC (xenograft model and ''DEN'' model), this work highlights the mobilization of the RNase activity of IRE1α dans HCC, and the inflammasome-dependent regulation of IRE1α-sXBP1.
We demonstrate the therapeutic benefit of pharmacological inhibitors of IRE1α "alone", in particular MKC8866 currently in phase 2 clinical trials in triple-negative breast cancer. In addition, these inhibitors reinforce the favorable properties of sorafenib: increased apoptosis, reduced viability, tumor progression and inflammasome activation. This combination leads to a significant reduction in tumor volume in vivo, via pro-apoptotic mechanisms paradoxically dependent on the UPR response itself, and also a reduction in systemic inflammation and the inflammasome.
This study opens up a new therapeutic perspective for HCC patients. The use of specific pharmacological inhibitors of IRE1α RNase activity would represent a novel therapeutic strategy in the treatment of HCC, a major public health issue.
HCC, liver cancer, IRE1α, UPR, NLRP3 inflammasome, pharmacological treatments
Pr Olivier SORIANI (IBV - Nice)
Pr Jean-Pierre COUTY (CRC – Paris)
Dr Laurent COMBETTES (IBAIC – Paris)
Dr Marie-Thérèse DIMANCHE-BOÎTREL (IRSET – Rennes)
Dr Fatima TEIXEIRA-CLERC (IMRB – Paris)
Thesis supervisor :
Dr. Béatrice BAILLY-MAÎTRE (C3M – Nice)