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Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.Metastatic dissemination can occur early during cancer progression, yet clinically overt metastases are often not detected for many years after surgical removal of the primary tumour. In this Perspective, Klein argues that understanding the ‘invisible’ phase of metastatic colonization is necessary to explain this phenomenon and develop better therapies to prevent metastasis.

Cancer is often regarded as a process of asexual evolution driven by genomic and genetic instability. Mutation, selection and adaptation are by convention thought to occur primarily within, and to a lesser degree outside, the primary tumour. However, disseminated cancer cells that remain after 'curative' surgery exhibit extreme genomic heterogeneity before the manifestation of metastasis. This heterogeneity is later reduced by selected clonal expansion, suggesting that the disseminated cells had yet to acquire key traits of fully malignant cells. Abrogation of the cells' progression outside the primary tumour implies new challenges and opportunities for diagnosis and adjuvant therapies.

Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.

Two related papers show that cells disseminated from malignant lesions at early time points during tumorigenesis can contribute to metastases at distant organs and provide insights into the molecular basis of dissemination. A potential mechanism for metastases The origin of metastases in cancer remains an open question. In a pair of linked papers, Christoph Klein, Julio Aguirre-Ghiso and colleagues now show in mouse models that cells disseminated from tumours early in tumorigenesis can contribute to metastases at distant organs at such early time points. Both papers also provide insights into the molecular basis of dissemination, which may be useful as targets to prevent metastasis. Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant 1 . Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours 2 . However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases 3 , 4 , 5 . These findings, and those in pancreatic cancer 6 and melanoma 7 models, indicate that dissemination might occur during the early stages of tumour evolution 3 , 8 , 9 . However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown 8 . Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2 + p-p38 lo p-Atf2 lo Twist1 hi E-cad lo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2 + eDCC precursors invaded locally, intravasated and lodged in target organs. Her2 + eDCCs activated a Wnt-dependent epithelial–mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1 hi E-cad lo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase.

Molecular single cell analyses provide insights into physiological and pathological processes. Here, in a stepwise approach, we first evaluate 19 protocols for single cell small RNA sequencing on MCF7 cells spiked with 1 pg of 1,006 miRNAs. Second, we analyze MCF7 single cell equivalents of the eight best protocols. Third, we sequence single cells from eight different cell lines and 67 circulating tumor cells (CTCs) from seven SCLC patients. Altogether, we analyze 244 different samples. We observe high reproducibility within protocols and reads covered a broad spectrum of RNAs. For the 67 CTCs, we detect a median of 68 miRNAs, with 10 miRNAs being expressed in 90% of tested cells. Enrichment analysis suggested the lung as the most likely organ of origin and enrichment of cancer-related categories. Even the identification of non-annotated candidate miRNAs was feasible, underlining the potential of single cell small RNA sequencing. Technologies for small non-coding RNA sequencing at the single-cell level are less mature than for sequencing mRNAs. Here the authors evaluate available protocols for analysis of circulating lung cancer tumour cells.

The pathogenesis of glioblastoma (GBM) is characterized by highly invasive behavior allowing dissemination and progression. A conclusive image of the invasive process is not available. The aim of this work was to study invasion dynamics in GBM using an innovative in vivo imaging approach. Primary brain tumor initiating cell lines from IDH-wild type GBM stably expressing H2B-Dendra2 were implanted orthotopically in the brains of SCID mice. Using high-resolution time-lapse intravital imaging, tumor cell migration in the tumor core, border and invasive front was recorded. Tumor cell dynamics at different border configurations were analyzed and multivariate linear modelling of tumor cell spreading was performed. We found tumor border configurations, recapitulating human tumor border morphologies. Not only tumor borders but also the tumor core was composed of highly dynamic cells, with no clear correlation to the ability to spread into the brain. Two types of border configurations contributed to tumor cell spreading through distinct invasion patterns: an invasive margin that executes slow but directed invasion, and a diffuse infiltration margin with fast but less directed movement. By providing a more detailed view on glioma invasion patterns, our study may improve accuracy of prognosis and serve as a basis for personalized therapeutic approaches.

Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of ~0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2 , are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets. For several cancer types, mouse models indicate that metastasis occurs early. Here, the authors show that human melanoma cells disseminate early and illustrate a genetic colonisation signature that evolves in parallel at different sites.

Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and therapy in systemic cancer. However, their infrequent and unreliable detection, especially in nonmetastatic cancer, currently impedes the clinical use of CTCs. Because leukapheresis (LA) targets peripheral blood mononuclear cells, which have a similar density to CTCs, and usually involves processing the whole circulating blood, we tested whether LA could substantially increase CTC detection in operable cancer patients. Therefore, we screened LA products generated from up to 25 L of blood per patient in two independent studies, and found that CTCs can be detected in more than 90% of nonmetastatic breast cancer patients. Interestingly, complete white blood cell sampling enabled determining an upper level for total CTC numbers of about 100,000 cells (median, 7,500 CTCs) per patient and identified a correlation of CTC numbers with anatomic disease spread. We further show that diagnostic leukapheresis can be easily combined with the US Food and Drug Administration-approved CellSearch system for standardized enumeration of CTCs. Direct comparison with 7.5 mL of blood revealed a significantly higher CTC frequency in matched LA samples. Finally, genomic single-cell profiling disclosed highly aberrant CTCs as therapy-escaping variants in breast cancer. In conclusion, LA is a clinically safe method that enabled a reliable detection of CTCs at high frequency even in nonmetastatic cancer patients, and might facilitate the routine clinical use of CTCs as in the sense of a liquid biopsy. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring of early systemic cancer.

When, in tumour progression, might metastasis be initiated? This Perspective argues that tumour cells disseminate early in malignant progression of the primary tumour so that disseminated tumour cells evolve the traits to allow growth within the metastatic site independently from the primary tumour. Systemic cancer progression is accounted for in two basic models. The prevailing archetype places the engine of cancer progression within the primary tumour before metastatic dissemination of fully malignant cells. The second posits parallel, independent progression of metastases arising from early disseminated tumour cells. This Perspective draws together data from disease courses, tumour growth rates, autopsy studies, clinical trials and molecular genetic analyses of primary and disseminated tumour cells in support of the parallel progression model. Consideration of this model urges review of current diagnostic and therapeutic routines.

Cancer resistance to targeted therapies seems to be a field of active research. But there are still open questions as to what drives drug resistance not only in metastatic tumor cells but also in disseminated tumor cells (DTCs) during adjuvant treatment, before metastases are established in other organs. Targeting this residual cancer disease or keeping these DTCs in a dormant state may be a way to stop progression to metastatic disease. For this, a further understanding of the biology of these cells is necessary. In 'Bedside to Bench', Bernhard Polzer and Christopher Klein put forward several scenarios to explain the different resistant mechanisms that might account for DTCs unresponsiveness to cancer drugs and emphasize the relevance of synchronizing targeted therapies with the changing responsive or dormant state of disseminated cancer cells in the clinic. In 'Bench to Bedside', Julio A Aguirre-Ghiso, Paloma Bragado and Maria Soledad Sosa discuss possible cell-intrinsic and microenvironment-derived signaling pathways that may be exploited to maintain dormancy in DTCs and explore the possibility of using dormancy gene signatures to identify individuals with dormant disease.