Hepatic Cell Biology

The major scientific contributions are in the areas of signaling pathways that determine cellular fate in growth arrest vis a vis cellular transformation. The key areas of scientific work include : (a) Identifying signalling mechanisms related to hepatocyte rejuvenation of senescent hepatocytes in end stage liver disease especially cirrhosis (b) identifying genetic drivers for hepatocellular cancer and gallbladder cancer, (c) Genetic based risk stratification in alcohol usage disorde

Work from the Lab on the Cover- Page of Journals

Senescence and Cancer: As ageing and cancer are at croosroads, the group has evaluated mechanisms that can prevent cellular senescence and impact progression towards cancer. The major highlights of the work include

• Accumulation of senescent cell in end stage liver diseases and involvement of mitochondrial unfolded protein response in ameliorating senescence ( Bijoya Sen et al, Cellular and Molecular Gastroenterology and Hepatology, 2019; On the Cover Page of CMGH, Young Investigator Award at AASLD, Patent applied)
• Senescent cells are inflammatory in nature and their presence in cancerous milieu leads to alterations in immune cell fate (Sen et al, Medical Oncology, 2022).
• Palmitate induced growth arrest in hepatocytes associated with disturbance of NAD+ dependent pathways ( Aggarwal et al, BBRC, 2024) and NAD+ at the crossroads connecting circadian rhythm and Sirtuins in context of fatty liver disease (Aggarwal et al, BBRC, 2023)

Translational Science on impact of Hepatocyte Senescence in liver disease prognosis

• In a collaborative work with Pediatric Hepatologists we have now used the senecnece markers In liver samples of pediatric acute liver failure and recently reported that greater number of senescent hepatocytes are associated with a poor outcome (Panda et al, Pediatr Transplant, 2024)
• Collaborating with pathologists and transplant surgeons, the study revealed that LDLT allograft biopsies highlighted the significance of biliary senescence in rejection, indicating a potential pathobiological link between senescence and the unfavorable prognosis observed in late acute cellular rejection and chronic rejection (Rastogi et al in JCEH, (2022).

Sirtuins in cellular senescence and cancer

The group has investigated the role of mammalian Sirtuin family, , NAD+-dependent histone deactylase in cellular senescence and its impact on cancer evolution. As there are seven different isoforms of Sirtuins (SIRT1-SIRT7) following significant contributions has been made on the cellular role of SIRT7 and SIRT2. Following are the key achievements:

• Identification of nuclear/ nucleolar targeting signals of SIRT7 and nucleolar loss of SIRT7 in replicative senescence ( Kiran et al., FEBS J, 2013)
• Identified the role of SIRT7 in altering cellular fate by preventing premature senescence via attenuating DNA damage response by regulating p53 response together with modulation of Stress Activated Protein Kianses activation ( Kiran et al., Expt Cell Res 2015).
• Identified a role of SIRT7 in Epithelial to Mesenchymal Transition with relevance to metastatic cell in homing ( Kiran et al, Frontiers in Oncology, 2020)
• SIRT2 was identified as a senescence associated marker (Anwar et al, Cell Cycle, 2016, Investigator award to student, Tarique, Cell Biology Meeting) , which is now currently been used to identify senescent hepatocytes in patients suffering from end stage liver disease or cirrhosis.
• Specific increase in levels of SIRT1 in cervical intraepithelial lesions make it a promising candidate for identification of preneoplastic changes in cancer cervix (Singh et al., Tumor Biol, 2015).
• Accumulation of senescent cell in end stage liver diseases and involvement of mitochondrial unfolded protein response in ameliorating senescence ( Bijoya Sen et al, Cellular and Molecular Gastroenterology and Hepatology, 2019; On the Cover Page of CMGH, Young Investigator Award at AASLD)
• Senescent cells are inflammatory in nature and their presence in cancerous milieu leads to alterations in immune cell fate (Sen et al, Medical Oncology, 2022).

Signaling pathways during neoplastic transformation:

• Dr. Gayatri Ramakrishna had previously proposed a role of wild type Ras in growth arrest (Singh et al, FASEB J, 2013) And this was supported by the observation on significantly low amounts of wild type Ras-p21 in hepatocellular carcinoma (Bose et al., Journal of Gastroenterology and Hepatology, 2011). These results have suggested a novel role of growth suppressive effects for the wild type Ras. A stochastic model for progression of hepatic cancer was proposed.
• Yet another major contribution is the identification of calcineurin signalling in cervical cancer. The work has unraveled activation of calcineurin-NFAT2 activation in cervical cancer by the oncoprotein of Human Pappiloma Virus ( Ram et al, Exp Cell Res, 2017) and further blocking this pathway using calcieurin inhibitor, cyclosporine A, resulted in non-apoptotic form of cell death in cancer cells. (Ram et al, BBA: Molecular Cell Res , 2014). This work has opened a new avenues for exploiting non-apoptotic forms as new drug target in cancer therapeutics, especially for neoplastic cells resistant to apoptosis such as liver cancer.

Images of Chemotherapy Induced Senescence

Taken from our published work : Sen et al, CMGH, 2020

Generation of Stable Hepatoma Cell Line expressing Mitochondrial Protease, ClpP

Taken from our published work : Sen et al, CMGH, 2020