Duke University Medical Center, In the context of cancer, the hypothesis that EMT and mesenchymaltoepithelial transition (MET) drive the invasionmetastasis cascade (Thiery, 2002) has been pursued enthusiastically for over a decade (Hartwell etal., 2006; Jung etal., 2008; Mani etal., 2007; Ocaa etal., 2012; Onder etal., 2008; Spaderna etal., 2008; Stankic etal., 2013; Tsai etal., 2012; Yang etal., 2004), but recent studies have questioned the indispensability of these transitions in establishing metastasis (Fischer etal., 2015; Shamir etal., 2014; Somarelli etal., 2016a; Zheng etal., 2015). (2015) genetically knocked out either Twist or Snail in a spontaneous pancreatic ductal adenocarcinoma (PDAC) model KPC model, but the incidence of metastasis was not altered significantly. Sarcomas are cancers of a mesenchymal lineage. Likewise, a longitudinal analysis of patients with adenocarcinoma that progresses to NEPC indicated that NEPC results from clonal evolution of an original adenocarcinoma through phenotypic plasticity (Beltran etal., 2016). While not a classic example of EMT, NEPClike tumors represent similar phenotypic plasticity, and some players implicated in EMT such as Snail have also been reported in the context of NEPClike tumors and neuroendocrine differentiation (McKeithen etal., 2011). These clusters of CTCs, although much less prevalent than individually migrating CTCs, can act as primary villains of metastasis by forming 50 times more tumors as compared to individual CTCs (Aceto etal., 2014). These observations lead us to inquire about the requirement of MET for metastasis. Taken together, although induction of at least a partial EMT at the invasive edges in primary xenografts has been observed invivo (Bonnomet etal., 2012; Klymkowsky and Savagner, 2009), a careful investigation of partial vs. full EMT needs to be conducted invivo to dissect the contributions of these phenotypic transitions to invasion, dissemination, and metastasis. In partial MET, cells are likely to retain their mesenchymal traits and gain their proliferative ability without the acquisition of any genetic alterations. HHS Vulnerability Disclosure, Help An official website of the United States government. An immunohistochemical study of 18 cases, Fang JH, Zhou HC, Zhang C, Shang LR, Zhang L, Xu J, Zheng L, Yuan Y, Guo RP, Jia WH, A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelialmesenchymal transitionindependent manner, Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC, Choi H, El Rayes T, Ryu S, Troeger J, Epithelialtomesenchymal transition is not required for lung metastasis but contributes to chemoresistance, Friedl P, Locker J, Sahai E and Segall JE (2012), Classifying collective cancer cell invasion, Futterman MA, Garca AJ and Zamir EA (2011), Evidence for partial epithelialtomesenchymal transition (pEMT) and recruitment of motile blastoderm edge cells during avian epiboly, GordonWeeks AN, Lim SY, Yuzhalin AE, Jones K, Markelc B, Kim KJ, Buzzelli JN, Fokas E, Cao Y, Smart S, Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2dependent angiogenesis in mice, Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells, Grigore A, Jolly MK, Jia D, FarachCarson M and Levine H (2016), Tumor budding: the name is EMT. Bethesda, MD 20894, Web Policies (B) In METindependent metastasis, therapy, epigenetic reprogramming, acquisition of novel mutations, or other mechanisms induce a postEMT state that becomes fixed in a proliferationhigh/invasionhigh phenotype. Therefore, with such ubiquitous tissue or even subtypespecific complexity and heterogeneity being revealed, binning carcinoma phenotypes into either fully epithelial or fully mesenchymal, and dismissing all hybrid phenotypes as metastable, can only hamper a better understanding of both the nuances of EMT and MET, and how these processes may impinge on metastasis. Therefore, the cells metastasizing independent of MET may be genomically unstable.
This instability may serve to enrich for the rare subset of cells that are likely to lead to dedifferentiated and highly metastatic tumors that are crossresistant to nextline therapies (Creighton etal., 2009; Sun etal., 2012). Overexpression of SNAI1 in MDCK and many carcinoma cell lines led to the loss of cellcell adhesion mediated by Ecadherin, transformed the morphology of cells from epithelial to spindlelike mesenchymal, and enhanced their migratory and invasive traits invitro (Batlle etal., 2000; Cano etal., 2000). sharing sensitive information, make sure youre on a federal The .gov means its official. abc disney company broadcasting american york walt west facts 66th history states wikipedia united usa upper headquarters side buys manhattan Although it is likely that many carcinomas undergo only a partial transition, some cancers reflect a more complete phenotypic transition based on typical morphological and molecular readouts. In a study comparing primary and metastatic tissue from breast and prostate cancer, Ecadherin was found at the cellular membranes more often in metastases than in primary tumors. states united anthem
1A). Phenotypic plasticity can be influenced by the tumor microenvironment; for instance, upregulation of hypoxia (Sun etal., 2009) and soluble factors released by macrophages and other infiltrating immune cells (Huang and Du, 2008; Toh etal., 2011) leads to upregulation of EMTTFs and EMT induction. Both genetic and nongenetic heterogeneity may be crucial or even synergistic in conferring a rare subpopulation of cells with high adaptability or plasticity that lets them transit the entire invasionmetastasis cascade. Further work revealed a similar, but less potent role of another EMTTF Slug (SNAI2, a member of the Snail family) both invitro and invivo (Bols etal., 2003; Hajra etal., 2002). Houston, SNAI1 was also shown to induce the expression of mesenchymal markers fibronectin and Zeb1 (Guaita etal., 2002), the latter of which is an EMTTF that can promote tumor invasiveness invitro and is correlated with tumor cell differentiation invivo (Aigner etal., 2007; Spaderna etal., 2008). These phenotypic transitions between states are not binary. Thus, it is not surprising that many carcinoma cells revert to an epitheliallike state when arriving to an epithelial environment to form metastases. Technically speaking, these studies were conducted with different approaches compared to spontaneous metastasis genetically engineered mouse models discussed above (Fischer etal., 2015; Zheng etal., 2015). Similar to carcinosarcomas, in which tumors exhibit admixture of two phenotypes, prostate tumors with areas of adenocarcinoma and neuroendocrine prostate cancer (NEPC) have also been observed. Therefore, active crawling or migration of cells driven by a partial or full EMT, often activated by overexpression of EMTTFs, is not certainly the only route to metastasis. It is possible that sarcoma cells are primed for enhanced metastatic capacity because of their mesenchymal lineage and that the acquisition of growth advantages during cancer initiation enables these cancers to metastasize readily via an METindependent route. It is also likely that each tumor's requirements for EMT/MET are slightly different depending on the original cell of origin (e.g., basal vs. luminal), its unique mutation profile (e.g., p53 loss), and its epigenetics (e.g., bivalent vs. monovalent chromatin). PMC legacy view For instance, in breast cancer, basal cells exhibit bivalent chromatin states, with both activating and repressive marks for a key EMTTF, ZEB1, but luminal cells only have repressive marks for ZEB1 (Chaffer etal., 2013). Many recent reports have suggested alternative mechanisms for the escape of carcinoma cells, besides the singlecell dissemination enabled by EMT. This hypothesis is based upon the observation that many metastases express epithelial markers (Christiansen and Rajasekaran, 2006). Representing EMT as a multidimensional nonlinear process. One of these cell lines, derived from an anaplastic, highly aggressive variant, led to the development of the anaplastic tumor 3 (AT3) cell line. Thus, retention of cellcell adhesion as an epithelial trait may actually be crucial to successful metastasis in many aggressive cancers.
For example, as shown in Fig. 8600 Rockville Pike MKJ would like to thank Anne GrosseWilde and Adrian Biddle for valuable discussions. Mechanisms underlying METindependent metastasis still remain elusive. Or do colonized tumor cells retain a high level of phenotypic plasticity, thereby priming them for multiple rounds of MET and EMT subsequent to metastatic seeding? More importantly, triplenegative breast cancer patients had a significantly higher number of such hybrid E/M cells as compared to other subtypes, suggesting a correlation between a hybrid E/M phenotype and tumor aggressiveness (Yu etal., 2013). Federal government websites often end in .gov or .mil. (2010) examined Ecadherin expression in primary breast tumors and matched metastases and found that 62% of cases had increased Ecadherin at the metastatic site compared to the primary tumor. Epithelialtomesenchymal transition (EMT) and its reverse mesenchymaltoepithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. 2A). Dotted lines represent phase separations. _located_on_the_Davis-Monthan_Air_Force_Base_in_Tucson%2C_Ariz.jpg/220px-thumbnail.jpg)
Inhibiting players that mediate cellcell adhesion directly or indirectly in these clusters such as plakoglobin or keratin 14 (K14) compromised their metastatic potential (Aceto etal., 2014; Cheung etal., 2016).
Together, these data suggest that metastasis for all carcinoma cells need not require an overt upregulation of various EMT markers to gain migratory and invasive traits. For example, factors such as hypoxia (Ju etal., 2017), tumorinfiltrating neutrophils (GordonWeeks etal., 2017), and radiation treatment (Bouchard etal., 2017; Ruegg etal., 2011) have been demonstrated to generate a metastasispromoting microenvironment. The idea that EMT need not be an allornone process (Nieto, 2013) has motivated a detailed dissection of different axes that cumulatively define EMT basement membrane remodeling, motility, cellcell adhesion, apical constriction, and loss of apicobasal polarity in sea urchin embryo. This mode would be instead of a postulated active crawling or migration of cancer cells into the circulation or toward any nutrient or chemokine gradient and cleavage of ECM by secreting proteases (Bockhorn etal., 2007) For instance, blood vessels have been proposed to engulf clusters of cancer cells, thus obviating the need for EMT (Fang etal., 2015). Induction of different EMTTFs may affect these five subcircuits or axes differently, and thus, there may be varying degrees of overlap in the gene expression profiles obtained after overexpression of EMTTFs. and transmitted securely. The other study (Fischer etal., 2015) focused on spontaneous breasttolung metastasis mouse models and used fibroblastspecific protein 1 (Fsp1) as a lineagetracing marker of cells undergoing an EMT. HL was also supported as a CPRIT (Cancer Prevention and Research Institute of Texas) Scholar in Cancer Research of the State of Texas at Rice University. Rice University, Similarly, deletion of TWIST1 drastically inhibited lung metastasis of 4T1 cells implanted in the mammary gland of recipient mice (Yang etal., 2004), emphasizing a causal role of EMTTFs in metastasis.
Some of these collectively invading cohorts referred as tumor buds displayed loss of cell polarity, reduced total levels and membrane localization of Ecadherin, and increased nuclear ZEB1. Also, although assumed here as independent axes, these five aspects of EMT may affect one another too, thus compounding the nonlinearity of the process. indians native 1764 bouquet american colonel council giving benjamin talk west near indian america seneca conference camp fire states americans Earlier studies based on similar overexpression of EMTTFs proposed an increase in tumorinitiating potential (Mani etal., 2008). In the context of cancer, Snail (SNAI1) was identified as the first EMTTF that directly repressed transcription of the epithelial cellcell adhesion molecule, Ecadherin. It is crucial that these cells are able to reactivate the cell cycle to proliferate and colonize; if the cells become fixed in a mesenchymallike phenotype and break the connection between the epithelial phenotype and cell cycle activation, either by mutation or by epigenetic reprogramming, their metastatic potential might be severely compromised (Fig. This work was supported by the National Science Foundation (NSF) Center for Theoretical Biological Physics (NSF PHY1427654), NSF PHY1605817, and NSF DMS1361411. Thus, EMT progression is not a unidimensional linear process, but a navigation through a rugged highly nonlinear landscape (Fig. Such hybrid E/M cells coexpressing various epithelial and mesenchymal markers have been observed in breast, ovarian, lung, and renal cell carcinoma cell lines (Andriani etal., 2016; GrosseWilde etal., 2015; Huang etal., 2013; Sampson etal., 2014; Schliekelman etal., 2015), in mouse models of prostate cancer and PDAC (Rhim etal., 2013; Ruscetti etal., 2015), primary breast and ovarian cancer tissue (Strauss etal., 2011; Yu etal., 2013), in the bloodstream of breast, lung, and prostate cancer patients (Armstrong etal., 2011; Lecharpentier etal., 2011; Yu etal., 2013), and in metastatic brain tumors (Jeevan etal., 2016). 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. A threedimensional reconstruction of serial section samples of many tumors has suggested that cell clusters are the predominant agents of invasion and that singlecell dissemination is extremely rare (Bronsert etal., 2014). Put together, it still remains a possibility that the traits needed for successful metastasis can be gained by altering cellular adhesion and invasion through pathways that do not necessitate supraphysiological or aberrant overexpression of one or more EMTTFs identified so far (Fig.
The invasive program comes at a cost; EMT induction leads to downregulation of proliferative potential (blue curve).
Invivo experimental evidence for these two models of metastatic progression was demonstrated using lethal reporters ofMET that kill all the cells undergoing MET.
There may be some overlap in the effect of more than one EMTTFs in regulation of one or more of these axes contributing to EMT, as can be realized by projecting this multidimensional space into two principal component axes (PCA). FOIA MKJ was supported by a training fellowship from the Gulf Coast Consortia on the Computational Cancer Biology Training Program (CPRIT Grant No. Accessibility NC, USA, 2 (A) In METdependent metastasis, postEMTlike cancer cells upregulate invasive programs that facilitate dissemination and seeding (red curve).
3). These clusters may avoid cell death in circulation by cellcell contactmediated survival signals (Shen and Kramer, 2004) and may already be enriched for players such as Jag1 (Cheung etal., 2016) that can help them evade multiple therapies (Boareto etal., 2016; Li etal., 2014; Shen etal., 2015; Simes etal., 2015) and colonize successfully (Sethi etal., 2011). This assumption was supported by the labeling of phenotypes coexpressing canonical epithelial and mesenchymal markers as metastable, strongly suggesting that these observations were a snapshot enroute to full EMT/MET and thus could not reflect a stable state or an end point of a transition in itself (Lee etal., 2006). Reestablishment of an epitheliallike phenotype via MET at the metastatic site awakens the proliferative potential necessary for the formation of macrometastases. This is an open access article under the terms of the, epithelialtomesenchymal transition, hybrid epithelial/mesenchymal, mesenchymaltoepithelial transition, metastasis, phenotypic plasticity, Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis, Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity, Amend SR, Roy S, Brown JS and Pienta KJ (2016), Ecological paradigms to understand the dynamics of metastasis, Andriani F, Bertolini G, Facchinetti F, Baldoli E, Moro M, Casalini P, Caserini R, Milione M, Leone G, Pelosi G, Conversion to stemcell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells, Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, Herold CI, Marcom PK, George DJ and GarciaBlanco MA (2011), Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers, Arnoux V, Nassour M, L'Helgoualc'h, Hipskind RA and Savagner P (2008), Erk5 controls Slug expression and keratinocyte activation during wound healing, Batlle E, Sancho E, Franc C, Domnguez D, Monfar M, Baulida J and De Herreros AG (2000), The transcription factor snail is a repressor of Ecadherin gene expression in epithelial tumour cells, Beerling E, Seinstra D, de Wit E, Kester L, van der Velden D, Maynard C, Schfer R, van Diest P, Voest E, van Oudenaarden A, Plasticity between epithelial and mesenchymal states unlinks EMT from metastasisenhancing stem cell capacity, Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BVSK, Varambally S, Divergent clonal evolution of castrationresistant neuroendocrine prostate cancer, Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets, Benedito R, Roca C, Srensen I, Adams S, Gossler A, Fruttiger M and Adams RH (2009), The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis, Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE and Mackenzie IC (2011), Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative, The significance of epithelial differentiation in mixed mesodermal tumors of the uterus. One hypothesis is based on recent observations that cells that fail to undergo cell cycle arrest upon induction of EMT accumulate genomic instability (Comaills etal., 2016). These results are reminiscent of the essential role of Ecadherin in forming tumor emboli and distant metastasis in inflammatory breast cancer (Tomlinson etal., 2001) a highly aggressive cancer that predominantly metastasizes via clusters (Kleer etal., 2001). Reconciling these contradictions, recent studies that categorized cells into E (epithelial), M (mesenchymal), and hybrid E/M, instead of just E and M, have proposed that tumorinitiating potential might be maximum when cells are in a hybrid E/M state (GrosseWilde etal., 2015; Jolly etal., 2014; Ombrato and Malanchi, 2014; Ruscetti etal., 2015).
This instability may serve to enrich for the rare subset of cells that are likely to lead to dedifferentiated and highly metastatic tumors that are crossresistant to nextline therapies (Creighton etal., 2009; Sun etal., 2012). Overexpression of SNAI1 in MDCK and many carcinoma cell lines led to the loss of cellcell adhesion mediated by Ecadherin, transformed the morphology of cells from epithelial to spindlelike mesenchymal, and enhanced their migratory and invasive traits invitro (Batlle etal., 2000; Cano etal., 2000). sharing sensitive information, make sure youre on a federal The .gov means its official. abc disney company broadcasting american york walt west facts 66th history states wikipedia united usa upper headquarters side buys manhattan Although it is likely that many carcinomas undergo only a partial transition, some cancers reflect a more complete phenotypic transition based on typical morphological and molecular readouts. In a study comparing primary and metastatic tissue from breast and prostate cancer, Ecadherin was found at the cellular membranes more often in metastases than in primary tumors. states united anthem
1A). Phenotypic plasticity can be influenced by the tumor microenvironment; for instance, upregulation of hypoxia (Sun etal., 2009) and soluble factors released by macrophages and other infiltrating immune cells (Huang and Du, 2008; Toh etal., 2011) leads to upregulation of EMTTFs and EMT induction. Both genetic and nongenetic heterogeneity may be crucial or even synergistic in conferring a rare subpopulation of cells with high adaptability or plasticity that lets them transit the entire invasionmetastasis cascade. Further work revealed a similar, but less potent role of another EMTTF Slug (SNAI2, a member of the Snail family) both invitro and invivo (Bols etal., 2003; Hajra etal., 2002). Houston, SNAI1 was also shown to induce the expression of mesenchymal markers fibronectin and Zeb1 (Guaita etal., 2002), the latter of which is an EMTTF that can promote tumor invasiveness invitro and is correlated with tumor cell differentiation invivo (Aigner etal., 2007; Spaderna etal., 2008). These phenotypic transitions between states are not binary. Thus, it is not surprising that many carcinoma cells revert to an epitheliallike state when arriving to an epithelial environment to form metastases. Technically speaking, these studies were conducted with different approaches compared to spontaneous metastasis genetically engineered mouse models discussed above (Fischer etal., 2015; Zheng etal., 2015). Similar to carcinosarcomas, in which tumors exhibit admixture of two phenotypes, prostate tumors with areas of adenocarcinoma and neuroendocrine prostate cancer (NEPC) have also been observed. Therefore, active crawling or migration of cells driven by a partial or full EMT, often activated by overexpression of EMTTFs, is not certainly the only route to metastasis. It is possible that sarcoma cells are primed for enhanced metastatic capacity because of their mesenchymal lineage and that the acquisition of growth advantages during cancer initiation enables these cancers to metastasize readily via an METindependent route. It is also likely that each tumor's requirements for EMT/MET are slightly different depending on the original cell of origin (e.g., basal vs. luminal), its unique mutation profile (e.g., p53 loss), and its epigenetics (e.g., bivalent vs. monovalent chromatin). PMC legacy view For instance, in breast cancer, basal cells exhibit bivalent chromatin states, with both activating and repressive marks for a key EMTTF, ZEB1, but luminal cells only have repressive marks for ZEB1 (Chaffer etal., 2013). Many recent reports have suggested alternative mechanisms for the escape of carcinoma cells, besides the singlecell dissemination enabled by EMT. This hypothesis is based upon the observation that many metastases express epithelial markers (Christiansen and Rajasekaran, 2006). Representing EMT as a multidimensional nonlinear process. One of these cell lines, derived from an anaplastic, highly aggressive variant, led to the development of the anaplastic tumor 3 (AT3) cell line. Thus, retention of cellcell adhesion as an epithelial trait may actually be crucial to successful metastasis in many aggressive cancers.
For example, as shown in Fig. 8600 Rockville Pike MKJ would like to thank Anne GrosseWilde and Adrian Biddle for valuable discussions. Mechanisms underlying METindependent metastasis still remain elusive. Or do colonized tumor cells retain a high level of phenotypic plasticity, thereby priming them for multiple rounds of MET and EMT subsequent to metastatic seeding? More importantly, triplenegative breast cancer patients had a significantly higher number of such hybrid E/M cells as compared to other subtypes, suggesting a correlation between a hybrid E/M phenotype and tumor aggressiveness (Yu etal., 2013). Federal government websites often end in .gov or .mil. (2010) examined Ecadherin expression in primary breast tumors and matched metastases and found that 62% of cases had increased Ecadherin at the metastatic site compared to the primary tumor. Epithelialtomesenchymal transition (EMT) and its reverse mesenchymaltoepithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. 2A). Dotted lines represent phase separations. Inhibiting players that mediate cellcell adhesion directly or indirectly in these clusters such as plakoglobin or keratin 14 (K14) compromised their metastatic potential (Aceto etal., 2014; Cheung etal., 2016). Together, these data suggest that metastasis for all carcinoma cells need not require an overt upregulation of various EMT markers to gain migratory and invasive traits. For example, factors such as hypoxia (Ju etal., 2017), tumorinfiltrating neutrophils (GordonWeeks etal., 2017), and radiation treatment (Bouchard etal., 2017; Ruegg etal., 2011) have been demonstrated to generate a metastasispromoting microenvironment. The idea that EMT need not be an allornone process (Nieto, 2013) has motivated a detailed dissection of different axes that cumulatively define EMT basement membrane remodeling, motility, cellcell adhesion, apical constriction, and loss of apicobasal polarity in sea urchin embryo. This mode would be instead of a postulated active crawling or migration of cancer cells into the circulation or toward any nutrient or chemokine gradient and cleavage of ECM by secreting proteases (Bockhorn etal., 2007) For instance, blood vessels have been proposed to engulf clusters of cancer cells, thus obviating the need for EMT (Fang etal., 2015). Induction of different EMTTFs may affect these five subcircuits or axes differently, and thus, there may be varying degrees of overlap in the gene expression profiles obtained after overexpression of EMTTFs. and transmitted securely. The other study (Fischer etal., 2015) focused on spontaneous breasttolung metastasis mouse models and used fibroblastspecific protein 1 (Fsp1) as a lineagetracing marker of cells undergoing an EMT. HL was also supported as a CPRIT (Cancer Prevention and Research Institute of Texas) Scholar in Cancer Research of the State of Texas at Rice University. Rice University, Similarly, deletion of TWIST1 drastically inhibited lung metastasis of 4T1 cells implanted in the mammary gland of recipient mice (Yang etal., 2004), emphasizing a causal role of EMTTFs in metastasis.
Some of these collectively invading cohorts referred as tumor buds displayed loss of cell polarity, reduced total levels and membrane localization of Ecadherin, and increased nuclear ZEB1. Also, although assumed here as independent axes, these five aspects of EMT may affect one another too, thus compounding the nonlinearity of the process. indians native 1764 bouquet american colonel council giving benjamin talk west near indian america seneca conference camp fire states americans Earlier studies based on similar overexpression of EMTTFs proposed an increase in tumorinitiating potential (Mani etal., 2008). In the context of cancer, Snail (SNAI1) was identified as the first EMTTF that directly repressed transcription of the epithelial cellcell adhesion molecule, Ecadherin. It is crucial that these cells are able to reactivate the cell cycle to proliferate and colonize; if the cells become fixed in a mesenchymallike phenotype and break the connection between the epithelial phenotype and cell cycle activation, either by mutation or by epigenetic reprogramming, their metastatic potential might be severely compromised (Fig. This work was supported by the National Science Foundation (NSF) Center for Theoretical Biological Physics (NSF PHY1427654), NSF PHY1605817, and NSF DMS1361411. Thus, EMT progression is not a unidimensional linear process, but a navigation through a rugged highly nonlinear landscape (Fig. Such hybrid E/M cells coexpressing various epithelial and mesenchymal markers have been observed in breast, ovarian, lung, and renal cell carcinoma cell lines (Andriani etal., 2016; GrosseWilde etal., 2015; Huang etal., 2013; Sampson etal., 2014; Schliekelman etal., 2015), in mouse models of prostate cancer and PDAC (Rhim etal., 2013; Ruscetti etal., 2015), primary breast and ovarian cancer tissue (Strauss etal., 2011; Yu etal., 2013), in the bloodstream of breast, lung, and prostate cancer patients (Armstrong etal., 2011; Lecharpentier etal., 2011; Yu etal., 2013), and in metastatic brain tumors (Jeevan etal., 2016). 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. A threedimensional reconstruction of serial section samples of many tumors has suggested that cell clusters are the predominant agents of invasion and that singlecell dissemination is extremely rare (Bronsert etal., 2014). Put together, it still remains a possibility that the traits needed for successful metastasis can be gained by altering cellular adhesion and invasion through pathways that do not necessitate supraphysiological or aberrant overexpression of one or more EMTTFs identified so far (Fig.
The invasive program comes at a cost; EMT induction leads to downregulation of proliferative potential (blue curve).
Invivo experimental evidence for these two models of metastatic progression was demonstrated using lethal reporters ofMET that kill all the cells undergoing MET.
There may be some overlap in the effect of more than one EMTTFs in regulation of one or more of these axes contributing to EMT, as can be realized by projecting this multidimensional space into two principal component axes (PCA). FOIA MKJ was supported by a training fellowship from the Gulf Coast Consortia on the Computational Cancer Biology Training Program (CPRIT Grant No. Accessibility NC, USA, 2 (A) In METdependent metastasis, postEMTlike cancer cells upregulate invasive programs that facilitate dissemination and seeding (red curve).
3). These clusters may avoid cell death in circulation by cellcell contactmediated survival signals (Shen and Kramer, 2004) and may already be enriched for players such as Jag1 (Cheung etal., 2016) that can help them evade multiple therapies (Boareto etal., 2016; Li etal., 2014; Shen etal., 2015; Simes etal., 2015) and colonize successfully (Sethi etal., 2011). This assumption was supported by the labeling of phenotypes coexpressing canonical epithelial and mesenchymal markers as metastable, strongly suggesting that these observations were a snapshot enroute to full EMT/MET and thus could not reflect a stable state or an end point of a transition in itself (Lee etal., 2006). Reestablishment of an epitheliallike phenotype via MET at the metastatic site awakens the proliferative potential necessary for the formation of macrometastases. This is an open access article under the terms of the, epithelialtomesenchymal transition, hybrid epithelial/mesenchymal, mesenchymaltoepithelial transition, metastasis, phenotypic plasticity, Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis, Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity, Amend SR, Roy S, Brown JS and Pienta KJ (2016), Ecological paradigms to understand the dynamics of metastasis, Andriani F, Bertolini G, Facchinetti F, Baldoli E, Moro M, Casalini P, Caserini R, Milione M, Leone G, Pelosi G, Conversion to stemcell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells, Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, Herold CI, Marcom PK, George DJ and GarciaBlanco MA (2011), Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers, Arnoux V, Nassour M, L'Helgoualc'h, Hipskind RA and Savagner P (2008), Erk5 controls Slug expression and keratinocyte activation during wound healing, Batlle E, Sancho E, Franc C, Domnguez D, Monfar M, Baulida J and De Herreros AG (2000), The transcription factor snail is a repressor of Ecadherin gene expression in epithelial tumour cells, Beerling E, Seinstra D, de Wit E, Kester L, van der Velden D, Maynard C, Schfer R, van Diest P, Voest E, van Oudenaarden A, Plasticity between epithelial and mesenchymal states unlinks EMT from metastasisenhancing stem cell capacity, Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BVSK, Varambally S, Divergent clonal evolution of castrationresistant neuroendocrine prostate cancer, Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets, Benedito R, Roca C, Srensen I, Adams S, Gossler A, Fruttiger M and Adams RH (2009), The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis, Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE and Mackenzie IC (2011), Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative, The significance of epithelial differentiation in mixed mesodermal tumors of the uterus. One hypothesis is based on recent observations that cells that fail to undergo cell cycle arrest upon induction of EMT accumulate genomic instability (Comaills etal., 2016). These results are reminiscent of the essential role of Ecadherin in forming tumor emboli and distant metastasis in inflammatory breast cancer (Tomlinson etal., 2001) a highly aggressive cancer that predominantly metastasizes via clusters (Kleer etal., 2001). Reconciling these contradictions, recent studies that categorized cells into E (epithelial), M (mesenchymal), and hybrid E/M, instead of just E and M, have proposed that tumorinitiating potential might be maximum when cells are in a hybrid E/M state (GrosseWilde etal., 2015; Jolly etal., 2014; Ombrato and Malanchi, 2014; Ruscetti etal., 2015).