Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways

Somarelli, Jason A.; Schaeffer, Daneen; Marengo, Matthew S.; Bepler, Tristan; Rouse, Doris J.; Ware, Kathryn E.; Hish, Alexander J.; Zhao, Yu; Buckley, Anne F.; Epstein, J.I.; Armstrong, Andrew J.; Virshup, David M.; García-Blanco, Mariano A.

doi:10.1038/onc.2015.497

Cited by 39 publications

(44 citation statements)

References 29 publications

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“…Thus, AT3 cells tend to reflect ‘epigenetically fixed’ EMT, reminiscent of the ‘epigenetically fixed’ mesenchymal state observed for human non‐small‐cell lung cancer H1703 or Calu6 cells upon prolonged exposure to TGF‐β (Thomson et al ., ). Yet, unlike the findings discussed above in which a complete EMT reduces the metastatic capacity of the cells, AT3 cells are highly metastatic and remain in a ‘fixed’ mesenchymal state during metastatic colonization (Somarelli et al ., ).…”

Section: Has a Full Emt Ever Been Seen In Vivo?mentioning

confidence: 99%

“…In vivo experimental evidence for these two models of metastatic progression was demonstrated using lethal reporters of MET that kill all the cells undergoing MET. These reporters revealed the existence of both METdependent and MET-independent paths to metastatic progressionan MET-dependent path in carcinosarcomas, whereas an MET-independent path in prostate cancer (Somarelli et al, 2016a). It is likely that EMT-TFs and microRNA families that maintain an epithelial phenotype (Bracken et al, 2008;Burk et al, 2008;Lu et al, 2013) regulate MET-dependent metastatic mechanisms.…”

Section: Is Met Required For Metastasis?mentioning

confidence: 99%

“…‘Transformation’ has given way to ‘transition’ and more recently ‘plasticity’ to accurately represent its reversibility as well as its nonbinary nature (Jolly et al ., ; Nieto et al ., ). In the context of cancer, the hypothesis that EMT and mesenchymal‐to‐epithelial transition (MET) drive the invasion–metastasis cascade (Thiery, ) has been pursued enthusiastically for over a decade (Hartwell et al ., ; Jung et al ., ; Mani et al ., ; Ocaña et al ., ; Onder et al ., ; Spaderna et al ., ; Stankic et al ., ; Tsai et al ., ; Yang et al ., ), but recent studies have questioned the indispensability of these transitions in establishing metastasis (Fischer et al ., ; Shamir et al ., ; Somarelli et al ., ; Zheng et al ., ). These results have stimulated provocative discussions on what steps are necessary and sufficient to establish macrometastases in vivo .…”

Section: Introductionmentioning

confidence: 99%

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EMT and MET: necessary or permissive for metastasis?

et al. 2017

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Epithelial‐to‐mesenchymal transition (EMT) and its reverse mesenchymal‐to‐epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial/mesenchymal plasticity has been observed preclinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial/mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT/MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models.

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Section: Has a Full Emt Ever Been Seen In Vivo?mentioning

confidence: 99%

Section: Is Met Required For Metastasis?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EMT and MET: necessary or permissive for metastasis?

et al. 2017

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“…Due to the limited information attained from available in vivo models, so far restricted to specific carcinoma mouse models (SCC, breast, pancreas, CRC), generalizations cannot be made. Indeed, some studies support that both plasticity-dependent and plasticity-independent mechanisms can operate in different cancer contexts (Brabletz, 2012b;Diepenbruck and Christofori, 2016;Somarelli et al, 2016). Therefore, additional studies using innovative genetically engineered mouse models to reliable trace and analyze tumor cells responsible for seed metastasis, together with implementation of higher-resolution in vivo intravital imaging microscopy, would certainly contribute to better understand the biological relevance of EMT and plasticity processes to metastasis in different tumor contexts.…”

Section: Models Of Intermediate E/m Statesmentioning

confidence: 99%

EMT: Present and future in clinical oncology

et al. 2017

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Epithelial/mesenchymal transition (EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting.

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“…Conversely, after reaching a distant organ, these cells have been proposed to undergo an MET (Mesenchymal to Epithelial Transition) -a reverse of EMT -to regain their traits of cell-cell adhesion and polarity to establish metastases 5 . However, an indispensable role of EMT and MET has been called into question recently [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

Jolly

Boareto

Debeb³

et al. 2017

Preprint

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Metastases claim more than 90% of cancer-related patient deaths and are usually seeded by a subset of circulating tumor cells (CTCs) shed off from the primary tumor. In circulation, CTCs are found both as single cells and as clusters of cells. The clusters of CTCs, although many fewer in number, possess much higher metastatic potential as compared to that of individual CTCs. In this review, we highlight recent insights into molecular mechanisms that can enable the formation of these clusters -(a) hybrid epithelial/mesenchymal (E/M) phenotype of cells that couples their ability to migrate and adhere, and (b) intercellular communication that can spatially coordinate the cluster formation and provide survival signals to cancer cells. Building upon these molecular mechanisms, we also offer a possible mechanistic understanding of why clusters are endowed with a higher metastatic potential. Finally, we discuss the highly aggressive Inflammatory Breast Cancer (IBC) as an example of a carcinoma that can metastasize via clusters and corroborates the proposed molecular mechanisms.

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Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways

Cited by 39 publications

References 29 publications

EMT and MET: necessary or permissive for metastasis?

EMT and MET: necessary or permissive for metastasis?

EMT: Present and future in clinical oncology

Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

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