Human Endogenous Retrovirus K in the Crosstalk Between Cancer Cells Microenvironment and Plasticity: A New Perspective for Combination Therapy

Abstract

Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed.

Keywords: cancer biomarker; cancer plasticity; cancer therapy; combination therapy; endogenous retroviruses; reprogramming; stemness; tumor microenvironment.

FIGURE 1

HERV-K as the master of melanoma plasticity in tumor adaptation to microenvironment. In response to different types of media, TVM-A12 melanoma cells change morphology and functional properties. The acquisition of undifferentiated and of stemness features under microenvironment alterations is HERV-K-dependent and related to increased malignancy, metastatic potential, and immune evasion.

FIGURE 2

HERV-K provides new avenues for combination therapy. (A) HERV-K and cancer hallmarks. In melanoma cells, microenvironment modifications lead to the increase of HERV-K transcriptional activity associated to cell plasticity and different hallmarks of cancer such as phenotype switching, stemness features, immune evasion, and metastatic properties. (B) HERV-K targeting in cancer combination therapy. Targeting HERV-K in association with conventional and innovative therapies such as immunotherapy, cell transdifferentiation/reprogramming-inducing agents, epigenetic modifiers and antiretrovirals, could shift the balance in the search for effective and less toxic cancer treatment.