Timeframe: 2022 – 2023
Goal: Identify functional role of mitochondrial alterations in FLC and FLC-Like BAP1 HCC
Principal Investigator: Jessica Zucman-Rossi, MD, PhD
Study overview: Recently, important research studies have reported specific genomic abnormalities of tumor subtypes. One of these, representing the fusion between DNAJB1 and PRKACA genes, has been described to be typical of the classic fibrolamellar subgroup. Another subgroup of tumors harboring fibrolamellar-like features was recently identified by the Inserm lab and was characterized by inactivating mutations of BAP1 encoding the BRCA1 associated protein-1 (FLC-Like BAP1 HCC). Despite the fact that these two subtypes of tumors harbor particular tumor histology and specific major gene alterations, they also share common features including PKA activation and absence of liver disease. Potentially, other similarities could exist. Mitochondria, which are often referred to as the powerhouses of the cell, are critical for many cellular functions including energy production, metabolism or cell survival. They have their own DNA called mitochondrial DNA or mtDNA. It has been reported that mitochondria number abnomalities and mtDNA sequence and copy number alterations were found in some tumors including FLC. However, their biological and clinical significances in FLC malignancy is poorly understood.
In this study, the team aims to understand the mitochondria alterations in FLC and FLC-like BAP1 HCC at different levels. Thus, they will study both the nuclear and mitochondrial DNA alterations, the number and the distribution of mitochondria within the tumor, paying attention to the functional consequences of the abnormalities. The findings should provide new insights in mitochondria significance in FLC, prioritizing next steps toward the development of novel and effective therapeutics.