Gallbladder cancer (GBC) is the most common biliary tract malignancy and is characterized by late diagnosis and poor prognosis. Efforts are needed to search for markers for early diagnosis and more effective therapeutic strategies.

Human endogenous retroviruses (HERVs) are viral “fossils” in the human genome that originated from the integration of ancient exogenous retroviruses and were inherited according to Mendelian laws of inheritance. They have been reported to be reactivated in a variety of cancers and involved in cancer development and immunotherapy. Exploring the potential of HERVs as diagnostic markers and therapeutic targets has attracted much attention. Whether HERVs have implications on GBC tumor microenvironment is worth exploring as it may provide insights into GBC clinical management. 

In a recent study published in eBioMedicine, Prof. CUI Jie’s group at Institut Pasteur of Shanghai of the Chinese Academy of Sciences explored the transcriptional landscape and potential functional impact of HERVs in gallbladder cancer by single-cell RNA sequencing.

Prof. CUI’s group first performed single-cell RNA sequencing (scRNA-seq) in GBC tumor and paired adjacent normal tissues to dissect the cellular diversity and delineate the HERV transcriptional landscape for GBC. HERVs were found to be aberrantly activated in tumor-derived cells and expressed in a cell type-specific manner, which contributes to the tumor heterogeneity. For each identified cell type, HERVs with significantly elevated expression and their associated biological functions were identified. 

In addition, Prof. CUI’s group experimentally confirmed that HERVs can serve as enhancers and potentially alter the expression of adjacent genes. The expression of HERVH was gradually increased as the malignant transformation of epithelial cells, suggesting that it may be a candidate for early diagnosis. HHLA2, which is derived by HERVH, was proposed that it may be an appealing target for GBC therapy. 

This study highlights the important role of HERVs in GBC and offers a novel perspective on cancer management.