The rate of new cases and death from primary liver cancer such as Hepatocellular Carcinoma (HCC) and cholangiocarcinoma (CCA) is alarmingly rising worldwide. To date, few treatment options are available and hence there is a critical need to identify new therapeutic targets for improving the long-term outcome of patients with advanced liver cancer.
The goal of our research team is to identify the hepatic factor/s executing the tumor initiation, progression and examine their therapeutic potential for the treatment of liver cancer. One such potential but the untested therapeutic hepatic factor is nuclear damage-associated molecular pattern (DAMP) proteins such as high-mobility group box 1 (HMGB1) protein. HMGB1 is released extracellularly and binds to the receptor for advanced glycation end products (RAGE) to stimulate liver progenitor cells and promote tumorigenesis. However, how HMGB1promotes hepatic tumorigenesis is less clear. Understanding the role of HMGB1in hepatic tumorigenesis is critical to therapeutically target HMGB1. Active release of HMGB1 from stressed hepatocytes can initiates and promotes hepatic tumorigenesis likely by 1) suppression of hepatocyte identity determine transcription factor such as HNF4a (increasing cellular plasticity) (tumor initiation) and 2) extrinsically modulating the tumor microenvironment through alteration of immune landscape (tumor promotion). We hypothesize that HMGB1 must be intact in the nucleus to facilitate the transcriptional activity of HNF4a.Alternatively, extracellular release of HMGB1 will result in loss of HNF4afunction, rendering hepatocytes more plastic. Extracellular HMGB1 will further alter the immune cell landscape by polarizing tumor-associated macrophages(TAM) and tumor associated fibroblasts (TAF) to initiate and promote hepatic tumors. Hence targeting HMGB1 could be a new, effective therapeutic approach for treating liver cancer. These outcomes of our study would also likely open new avenues for future clinical trials against nuclear DAMPS such as HMGB1 in the context of liver cancer.
Education: MS, PHD
ORCID identifier: https://orcid.org/0000-0002-9432-2064
MyNCBI Link: bilon KHambu - Search Results - PubMed(nih.gov)
Selected Publications
o ByrnesK¶, Bailey NT¶, Baral K¶, Mercer A, Joshi S,Liu G, Yin XM, and Khambu B. Impaired hepatic autophagy exacerbates hepatotoxin induced liver injury. Cell Death Discovery.9, 71 (2023).
o Byrnes K, Blessinger S, Bailey N, Scaife R,Liu G, and Khambu B. Therapeutic regulation of autophagy in hepatic metabolism. ActaPharmaceutica Sinica B. 2022,12(1):33-49.https://doi.org/10.1016/j.apsb.2021.07.021
o Khambu B*, Hong H, Liu S, Liu G, Chen X, Dong Z,Wan J, Yin XM. The HMGB1-RAGEaxis modulates the growth of autophagy-deficient hepatic tumors. Cell Death and Disease 2020,11(5):333.PMCID: PMC7206028 (*CorrespondingAuthor).
o KhambuB, L.T., Yan S, Yu C,Chen X, Goheen M, Li Y, Lin J, Cummings OW, Lee YA, Friedman S, Dong Z, FengGS, Wu S, Yin XM, Hepatic Autophagy Deficiency Compromises FXR Functionalityand Causes Cholestatic Injury. Hepatology,2019; 69(5):2196-2213. PMCID: PMC6461497
o LeeYM, Noon LA, Akat K, Ybanez M, Lee TF, Berres ML, Fujiwara N, Goossens N, Chou H,Parvin-Nejad F, Khambu B,Kramer E, Gordon R, Pfleger C, Germain D, John G, Campbell K, Yue Z, Yin XM,Cuervo AM, Czaja M, Fiel M, Hoshida Y, and Friedman S. Autophagy is aGatekeeper of Hepatic Differentiation and Carcinogenesis by Controlling theDegradation of Yap. Nat Commun.2018;23(9):4962. PMCID: PMC6251897
o KhambuB, Huda N, Chen X,Antoine DJ, Li Y, Dai G, Dong Z, Zong WX, Waguri S, Köhler UA, Werner S, OuryTD, Yin XM. HMGB1 promotes ductular reaction and tumorigenesis inautophagy-deficient livers. J Clin Invest. 2018 June1;128(6):2419-2435. PMCID: PMC5983330
Keywords/Tags: livercancer, HCC, DAMP, HMGB1, DEK
Website: https://medicine.tulane.edu/departments/pathology-laboratory-medicine/faculty/bilon-khambu-msc-phd
