Series on Tumour Metastasis

Celia-Terrassa and Kang discuss specialized functions of distinct metastatic niches, and how the emerging knowledge can be leveraged for improved therapeutic opportunities.

Goddard et al review recent advances in our understanding of dormant tumour cells, highlight their cross-talk with immune responses, and elaborate therapeutic implications to treat metastatic malignancies.

Lawson et al. review recent advances in single-cell technologies and discuss in detail how they can be leveraged to understand tumour heterogeneity and metastasis.

Understanding the dynamics and complexity of tumour metastasis is crucial for improving clinical interventions and care for cancer patients. In this issue, we present the first of a Series of commissioned Review articles that discuss emerging concepts, technological advances and therapeutic implications in this exciting field.

Massagué and colleagues show that disseminated cancer cells use L1CAM to spread on capillaries and to achieve their outgrowth through activating YAP signalling.

Reeves et al. use a multistage skin carcinogenesis mouse model and multicoloured lineage tracing to analyse the different patterns of clonal evolution and behaviour seen in progressing and non-progressing papillomas.

Yeh et al. find that PSPC1 is upregulated in cancer and interacts with Smad2/3 to induce TGF-β1. This leads to increased autocrine TGF-β1 signalling and a switch to pro-metastatic TGF-β1-dependent gene expression.

Zajac et al. show that in colorectal cancer, decreased TGF-β signalling promotes apical actomyosin contractility and collective apical budding of invading tumour spheres with inverted polarity that drive metastatic spread.

Gawrzak et al. show that MSK1 regulates bone metastatic dormancy of ER⁺ breast cancer. MSK1 affects histone modifications at luminal transcription factor promoters to prevent cell differentiation and bone homing.

Lee et al. found that the ubiquitin-editing enzyme A20 promotes TGF-β1-induced EMT and metastases of breast cancer cells via ubiquitylation-mediated nuclear stabilization of Snail1.

Zhuang et al. show that breast-cancer-secreted DKK1, while promoting bone metastases via canonical WNT signalling, inhibits lung metastasis by antagonizing non-canonical Wnt signalling to suppress recruitment of anti-tumour immune cells.

Grelet et al. find that hnRNP E1 release from PNUTS pre-RNA in response to TGFβ generates a lncRNA that acts as competitive sponge for miR-205, promoting epithelial–mesenchymal transition in cancer.

Joyce and colleagues report that obesity promotes lung neutrophilia in mice, which in the presence of a primary breast tumour fosters metastasis to the lung in a manner dependent on GM-CSF and IL5.

Celià-Terrassa et al. find that by repressing LCOR, a modulator of the interferon response, miR-199a allows both normal and cancer mammary stem cells to evade senescence and differentiation, thus promoting tumorigenesis.

Adding to the recent debate on the role of epithelial–mesenchymal transition (EMT) in cancer cell invasion and metastasis, Brabletz and colleagues show that the EMT-inducing transcription factor Zeb1 drives pancreatic tumorigenesis and metastasis.

Cancer-associated fibroblasts (CAFs) promote metastasis by creating tracks for cancer cell migration. Labernadie et al. now show that heterotypic adhesions between E-cadherin on cancer cells and N-cadherin on CAFs transmit forces to drive invasion.

Li et al. show that ROR1–HER3 receptor tyrosine kinase signalling in breast cancer cells inhibits the MST1/2 Hippo pathway kinases through a lncRNA termed MAYA. The resulting activation of YAP promotes osteoclast differentiation for bone metastasis.

Aguirre-Ghiso and colleagues report that hypoxia in the primary tumour microenvironment leads to upregulation of a dormancy signature in the tumour cells that persists after their dissemination to distant sites, permitting them to evade therapy.

Lin and colleagues report that hypoxia induces TRAF6-dependent mono-ubiquitylation of histone H2AX, which promotes binding and stabilization of HIF1α. Activated HIF1α signalling in turn promotes tumorigenesis and metastasis.

Johnson et al. report that loss of leukaemia inhibitory factor receptor (LIFR) signalling reduces the expression of genes associated with dormancy in metastatic breast cancer cells, and promotes bone marrow colonization and osteoclastogenesis.

Torrano et al. use bioinformatics analyses to identify PGC1α as a transcriptional regulator of a metabolic program downstream of ERRα that opposes metastatic dissemination in prostate cancer.

Nielsen et al. show that granulin is secreted by metastasis-associated macrophages to promote pancreatic cancer metastasis. Granulin activates hepatic stellate cells, which secrete periostin, thereby resulting in a fibrotic, pro-metastatic liver milieu.

Metastatic colonization of distant organs is the prime cause of mortality from cancer, and is governed by a series of steps that include survival and growth in the perivascular niche. A study now shows that L1CAM is necessary for tight physical interactions in this niche, involving a YAP–MRTF–β1-integrin mechanotransduction pathway.

Multiple clones of cancer cells co-exist within a tumour, and yet it is not clear when these subclones arise and how they contribute to tumour progression. A multicolour clonal tracing study now shows that benign skin tumours are mostly monoclonal while the more advanced lesions are composed of multiple intermixed subclones.

The roles of transforming growth factor β (TGF-β) depend on the cellular context. Paraspeckle component 1 now arises as a driver of epithelial-to-mesenchymal transition and stemness transcription factors to redirect effectors from tumour suppressive to pro-metastatic gene promoters, emerging as a contextual determinant of TGF-β function.

Intrinsic factors that regulate dormancy of disseminated tumour cells (DTCs) are predominantly unknown. Now, knockdown of MSK1 is shown to accelerate bone metastasis of luminal breast cancer cells. MSK1 acts through epigenetic mechanisms that enforce the luminal phenotype and promote steady-state maintenance of DTCs within bone.

Cancer cells preferentially metastasize to certain organs. A study in mouse models of breast cancer shows that the DKK1 negative regulator of WNT signalling inhibits tropism to the lung, but enhances tropism to the bone due to the differential regulation of canonical and non-canonical WNT signalling in the two microenvironments.

Little is known regarding how the interactions of stem cells with the immune system regulate their plasticity. A study now describes a mechanism by which normal breast and cancer stem cells utilize miR-199a to downregulate the corepressor LCOR and minimize responses to type I interferon.

The role of the epithelial-to-mesenchymal transition in tumour progression remains a topic of intense debate. Now, data on the role of Zeb1 in the metastatic spread of pancreatic cancer clarify apparently conflicting views by revealing context-specific, differential use of individual epithelial-to-mesenchymal transition transcription factors in cancer cell dissemination.

Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression. The previously uncharacterized lncRNA MAYA is now shown to promote bone metastasis by bridging ROR1–HER3 and Hippo–YAP pathways. Neuregulin-induced HER3 phosphorylation by ROR1 recruits a MAYA-containing protein complex to methylate Hippo/MST1 and activate YAP target genes that are essential for bone metastasis.

Metabolic rewiring is essential for cancer cell survival. PGC1α, a transcriptional co-activator that is downregulated in prostate cancer, is now shown to control prostate cancer metabolism by activating an oxidative metabolic program that prevents tumour growth and metastatic dissemination.

The liver is the most common metastatic route of pancreatic cancer. Early recruitment of granulin-secreting inflammatory monocytes to the liver is now shown to reprogram hepatic stellate cells into myofibroblasts that modulate the liver microenvironment to support the growth of metastasizing tumour cells.