Deciphering molecular mechanisms of metastasis: novel insights into targets and therapeutics

Abstract

Background: The transition of a primary tumour to metastatic progression is driven by dynamic molecular changes, including genetic and epigenetic alterations. The metastatic cascade involves bidirectional interactions among extracellular and intracellular components leading to disintegration of cellular junctions, cytoskeleton reorganization and epithelial to mesenchymal transition. These events promote metastasis by reprogramming the primary cancer cell's molecular framework, enabling them to cause local invasion, anchorage-independent survival, cell death and immune resistance, extravasation and colonization of distant organs. Metastasis follows a site-specific pattern that is still poorly understood at the molecular level. Although various drugs have been tested clinically across different metastatic cancer types, it has remained difficult to develop efficacious therapeutics due to complex molecular layers involved in metastasis as well as experimental limitations.

Conclusions: In this review, a systemic evaluation of the molecular mechanisms of metastasis is outlined and the potential molecular components and their status as therapeutic targets and the associated pre-clinical and clinical agents available or under investigations are discussed. Integrative methods like pan-cancer data analysis, which can provide clinical insights into both targets and treatment decisions and help in the identification of crucial components driving metastasis such as mutational profiles, gene signatures, associated pathways, site specificities and disease-gene phenotypes, are discussed. A multi-level data integration of the metastasis signatures across multiple primary and metastatic cancer types may facilitate the development of precision medicine and open up new opportunities for future therapies.

Keywords: Circulating tumour cells; Epithelial‐mesenchymal transition; Metastasis; Pan‐cancer analysis; Precision medicine; Secondary tumour.