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Over 9 million deaths occur from metastatic tumours worldwide each year. Metastasis is generally regarded as uncurable, and as such is a major clinical and societal burden. From recent basic and translational research, a growing armamentarium of targeted therapeutics have emerged selective for one of the hallmark properties associated with metastasis. The multi-step process of invasion and metastasis has been described as discrete steps1, but over the past decade our understanding of the complexity of the process has increased significantly. One hallmark of the process is tumour plasticity, and the role of contextual signals and microenvironmental cues in moulding tumour responses to therapy. Plasticity can lead to the rapid emergence of adaptive or acquired therapeutic resistance mechanisms and is a major barrier to the successful maintenance of patients with metastatic cancer. Thus, metastasis remains the leading cause of cancer-associated death. A more detailed understanding of the metastatic process will undoubtedly suggest new precision targeting and therapeutic avenues to meet this unmet clinical need.

In this special issue on Metastasis we have a number of timely reviews on various aspects of metastasis, including differing hallmarks of cancer as they relate to metastasis, as updated by Hanahan and Weinberg in 2011.2 The role of mitochondria as determinants of metastasis, including motility and invasion, the tumour microenvironment, plasticity and colonization at distant sites is reviewed by Scheid et al.3 These authors focus on how mitochondria tune metabolic and genetic responses to microenvironmental cues to enhance survival at distant cites. Of note, they stress that mitochondria can be both beneficial and detrimental to metastatic cells, and that mitochondria are involved in multiple critical steps in metastasis. One of the unanswered questions is how mitochondria affect the nuclear compartment, other cancer cells, and tumour stromal cells. Kumar et al. focus on the role of mitochondrial oxidative phosphorylation in a specific cancer, cutaneous melanoma.4 They detail how mitochondrial transfer from melanoma stem cells to tumour cells plays a key role in progression, in spite of dysfunctional mitochondrial mutations. They assert that targeting mitochondrial trafficking as a novel therapeutic approach for this disease that is classically refractive to long-term treatment with poor prognosis.

Patel et al. provide an elegant review on the genomic control of metastasis.5 Although metastasis can be driven by mutations found within the primary tumour, it has become clear in the last few years that the phenotypic output of driver mutations is variable between metastatic clones, requiring the input of epigenetic events that determine the transcriptome relevant for distant metastasis. From the various published cancer genome studies, it is apparent that mutational patterns remain tissue-specific. The authors suggest that the identification of genetic and epigenetic biomarkers for early detection of metastasis will require a better understanding of how the tissue-specific physiological programs interact with tumour selective mutational changes.

A regulatory program called the “epithelial–mesenchymal transition” (EMT), is a means by which transformed epithelial cells acquire the enabling capabilities to invade and disseminate to distant sites. Of note, the EMT program can be activated either transiently or stably during tumour progression, leading to differing opinions concerning its role as a dominant determinant of metastasis. Coban et al. review how tissue mechanics in the tumour microenvironment contribute to the process of EMT in tumour cells, and how this dynamic interplay drives the earliest steps of metastasis and significantly contribute to tumour plasticity.6 They purport that disrupting tumour microenvironmental-tumour interactions is a promising new area for therapeutic intervention. We also know that EMT-inducing transcriptional factors can orchestrate many of the steps of invasion and metastasis. Peyre et al. discuss how death signals from the TNF-related apoptosis-inducing ligand TRAIL impacts response to cancer therapeutics via an impact on EMT.7 They review het the contribution of a number of EMT-inducing transcription factors, including ZEB1/2, TWIST1, and MMTs, as well as factors secreted by carcinoma-associated fibroblasts (TGF-β, matrix metalloproteinases, HGF and uPA) that are impacted by EMT. They also summarize how this communication between cancer cells exploiting EMT and the microenvironmental cues contribute to response heterogeneity.

The problem of tumour dormancy, where latent cancer cells can persist for years after initial surgical removal of primary tumours, can unpredictably erupt and generate viable distant metastasis, is imbedded in the concept of cancer stem cells (CTCs or disseminated tumour cells [DTCs]) that are inherently resistant to therapeutic killing and can regenerate a tumour after therapeutic intervention. Riggio et al. expertly explore the “Lingering Mysteries of Metastatic Recurrence in Breast Cancer,” focusing on molecular and phenotypic properties of DTCs to examine which may be indolent or to identify those that contribute to metastatic recurrence.8 Strategies to prevent, reverse, prolong and eradicate dormancy will require novel approaches and clinical trial designs to exploit the “smoking gun” of DTC tumour dormancy. Perea Paizel et al. review adaptations developed by CTCs to survive the mechanical constraints in the microvasculature, and how these forces provide a selection for CTC adaptation.9 These authors review how targeting these CTC adaptations within capillaries may be a new promising approach to blocking metastatic progression.

We would like to highlight two reviews concerning the immune tumour microenvironment. Infiltrating cells of the immune system contribute to tumour behaviour in many ways. They can operate to antagonize or promote tumour progression, via enhancement of cancer hallmark properties. Many liken the influence of the tumour immune microenvironment as “wounds that never heal.” Boulter et al. discuss the fibrotic and immune microenvironment as new targetable driver of metastasis, using the liver as an example metastatic site and intravital imaging as new approach to investigate the dynamic nature of the communication between distant metastasis and the microenvironment.10 Edwards et al. focus on experimental model systems for studying the immune response during metastasis, and present a general review of the obstacles of using immunotherapy to treat metastatic disease.11 Accordingly, the authors emphasize the importance of creating animal models, such as humanized mice, that can recapitulate the evolution of the immune response as seen in patients with late-stage metastatic disease.

There are a number of outstanding original research contributions in the Metastasis Special Issue. Vasaikar et al. from Dr. Sendurai Mani’s laboratory present a publicly available, web-based resource for pan-cancer analysis of EMT genes and signatures, available at www.emtome.org.12 The EMTome database consists of cell line data from the Broad Institute and patient datasets from online resources for identifying metastasis-related features, EMT-related markers, and EMT signatures. This resource is unique, and will prove very valuable to researchers working on EMT, CTCs, and tumour dormancy. Yu et al. explore the role of CDX2, a member of the caudal-related homeobox transcription factor gene family, in the EMT in colorectal cancer.13 They report that CDX2 transactivates PTEN, thereby suppressing signalling through the PI3K/AKT/GSK-3β pathway. These effects decrease the EMT transcription factors Snail, Slug and ZEB1, and initiating a cascade of effect downstream of E-cadherin. The authors also confirmed these findings and associations in a cohort of colorectal cancer patients.

Tumour suppressor genes that limit cell growth and proliferation were characteristically discovered thru their inactivation of tumorigenesis via loss-of-function; two prototypical tumour suppressors are RB and TP53. Metastasis suppressors were similarly identified, but have been difficult to target therapeutically. Two authors present original evidence of metastasis-suppressor activity of selective genes. Young et al. explore the role of secretion of ITIH5, that encodes a heavy chain component of one of the inter-alpha-trypsin inhibitor (ITI) family members and is involved in extracellular matrix stabilization.14 ITIH5 was previously shown to be a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models; herein they demonstrate that suppression of liver metastasis involves an intracellular mechanism via deletion of the N-terminal secretion sequence. Targeting ITIH5 biology might represent a new therapeutic avenue in liver metastasis. Pamidimukkala et al. evaluate the metastasis-suppressor activity of the mouse Nme1 and Nme2 genes using a spontaneous in vivo metastasis model.15 NME1 was one of the first metastasis-suppressor genes identified in multiple cancer types. The authors assessed metastasis-suppressor activities of the individual Nme1 and Nme2 genes in UV-induced melanoma mouse model. The authors conclude that the robust metastasis-suppressor activities exhibited by both Nme1 and Nme2 provides compelling evidence for their individual roles in malignant melanoma progression.

The translational potential of targeting metastasis-inducing activities are highlighted in two original manuscripts included in the Special Issue. Using single-cell RNA-Seq of primary and metastatic tumours from breast cancer patient-derived xenografts (PDX), Dwyer et al. demonstrate the enrichment of phosphorylated progesterone receptor (PR) and downstream signalling via the insulin growth factor receptor pathway in both distant metastases and endocrine therapy-resistant models.16 Importantly they utilized a small molecule inhibitor of IRS-1, NT157, to block stem cell properties and endocrine resistance. Since this inhibitor blocked signalling from both insulin growth factor receptor and insulin receptor, it represents a novel strategy to target phospho-PR-specific signalling in ER+ breast cancer, particularly in endocrine-resistant, metastatic patients. In Dustin et al. the investigators utilized kinome proteomic and transcriptional profiling to investigate intrinsic endocrine resistance of cells and PDX models with mutations in the ESR1 gene.17 They demonstrate a shared transcriptional signature between ESR1 mutant and wild-type ER cells resistant to the CDK4/6 inhibitor palbociclib, that included upregulation of receptor tyrosine kinases. They focused on inhibition of the RON/PI3K pathway and successfully inhibited distant metastasis in PDX models with the RON inhibitor ASLAN002. Their results demonstrate that intrinsic endocrine therapy resistance driven by ESR1 mutations also predict resistance to CDK4/6 inhibitor therapy, and elect the use of selective inhibitors to RON as a new therapeutic approach in ESR1 mutant and/or palbociclib-resistant metastatic breast cancer patients.

Outlook

There remain many unanswered questions concerning the intricacies of invasive and metastatic phenotypes. Undoubtedly, genomic alterations account for only a part of the picture that includes the tumour microenvironment, the immune microenvironment, tumour dormancy, plasticity, EMT and cancer stem cells. Some of these phenotypes, such as EMT, have proven difficult to directly target, and it is expected that an understanding of downstream EMT processes will afford new therapeutic targets. We do know that therapeutic approaches focused only on properties inherent to primary tumours, will not provide optimum tumour control of metastasis for all cancer types. Precision targeting in metastatic cancer patients has great clinical promise, and it is hoped that identification of genes essential for metastatic progression, for instance genes involved in maintenance of tumour dormancy or tumour immune suppression, will provide more useful therapeutic options.