Unravelling the complexity of metastasis - molecular understanding and targeted therapies

Abstract

Despite recognizing the devastating consequences of metastasis, we are not yet able to effectively treat cancer that has spread to vital organs. The inherent complexity of genomic alterations in late-stage cancers, coupled with numerous heterotypic interactions that occur between tumour and stromal cells, represent fundamental challenges in our quest to understand and control metastatic disease. The incorporation of genomic and other systems level approaches, as well as technological breakthroughs in imaging and animal modelling, have galvanized the effort to overcome gaps in our understanding of metastasis. Future research carries with it the potential to translate the wealth of new knowledge and conceptual advances into effective targeted therapies.

Figure 1 |. Research strategies for understanding the molecular basis of cancer metastasis: from reductionism to systems biology.

The evolving states of cancer, including metastasis, are reflected in dynamically changing expression patterns of the genes and proteins within the cancer cells. Metastasis research has generally relied on the linear approach of gene-to-trait mapping, which links the metastasis genotype with its corresponding metastatic phenotype (part a). More complex linear linkages may include multivalent relationships, in which one gene (or group of genes) can have functions in multiple metastasis phenotypes (pleiotropy), and a metastasis tissue tropism can be exerted by many independent genes or gene groups (redundancy) (part b). However, gene interactions are influenced by their context, which often cannot be captured by traditional one-gene-one-trait approaches. Therefore, metastatic behaviour should be considered as the consequence of the collective action of individual metastasis genes through nonlinear interactions (part c). Understanding the nature of these network level interactions and identifying crucial nodes of functional control will pave the way towards rational therapeutic design for metastatic breast cancer. Red circles represent genes or groups of genes that mediate tissue-specific metastasis of breast cancer. Blue circles represent regulators of metastasis genes. Yellow circles represent key functional nodes of metastasis regulation networks and are prime targets for therapeutic development. The black, grey and dashed arrows indicate different pathways.

Figure 2 |. Evolving view of the dynamic relationship between the primary tumour and metastasis.

a | The traditional view of cancer metastasis in which primary tumour cells escape their site of origin, travel in a unidirectional path away from the primary site and ultimately colonize distant organs to give rise to systemic disease is shown. b | A dynamic view of cancer metastasis in which bone marrow-derived cells are mobilized by tumour-derived inflammatory factors and prime distant sites of metastasis to form the pre-metastatic niche is shown. Disseminated tumour cells (DTCs) (either from the primary tumour or from metastases) that have been selected with enhanced malignancy can colonize distant organs, as well as repopulate the primary site through the phenomenon of self-seeding.

Timeline |. The major technological breakthroughs and conceptual advances in cancer metastasis research

Black boxes denote technological advances, blue boxes denote conceptual advances and red boxes denote therapeutic advances. 2D, two-dimensional; ChIP, chromatin immunoprecipitation; FDA, US Food and Drug Administration; MALDI, matrix-assisted laser desorption/ionization; NIH, US National Institutes of Health; TMA, tissue microarray; VEGF, vascular endothelial growth factor.

Timeline |. The major technological breakthroughs and conceptual advances in cancer metastasis research

Black boxes denote technological advances, blue boxes denote conceptual advances and red boxes denote therapeutic advances. 2D, two-dimensional; ChIP, chromatin immunoprecipitation; FDA, US Food and Drug Administration; MALDI, matrix-assisted laser desorption/ionization; NIH, US National Institutes of Health; TMA, tissue microarray; VEGF, vascular endothelial growth factor.