EMT in Metastasis: Finding the Right Balance
2018; Elsevier BV; Volume: 45; Issue: 6 Linguagem: Inglês
10.1016/j.devcel.2018.05.033
ISSN1878-1551
AutoresHin Ching Lo, Xiang H.-F. Zhang,
Tópico(s)Renal and related cancers
ResumoThe epithelial-to-mesenchymal transition (EMT) is a key driver of cancer metastasis. In this issue of Developmental Cell, Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar demonstrate that an EMT mechanism involving protein internalization impacts cell migration, while Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar identify epithelial plasticity as a determinant of metastatic organotropism in pancreatic cancer. The epithelial-to-mesenchymal transition (EMT) is a key driver of cancer metastasis. In this issue of Developmental Cell, Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar demonstrate that an EMT mechanism involving protein internalization impacts cell migration, while Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar identify epithelial plasticity as a determinant of metastatic organotropism in pancreatic cancer. Cancer metastasis requires multiple steps, including local invasion, intravasation, and colonization of distant organs. To overcome the unique challenges of each step, cancer cells must exhibit phenotypic plasticity to adapt to their complex and changing environment. The epithelial-to-mesenchymal transition (EMT) is a developmental program exploited by cancer cells (Nieto et al., 2016Nieto M.A. Huang R.Y.Y.J. Jackson R.A.A. Thiery J.P.P. EMT: 2016.Cell. 2016; 166: 21-45Abstract Full Text Full Text PDF PubMed Scopus (2751) Google Scholar) to transition from a sessile epithelial state to a motile, invasive mesenchymal state, facilitating escape from the primary tumor. Importantly, this process is reversible by mesenchymal-to-epithelial transition (MET), enabling cancer cells to regain epithelial properties for outgrowth at distal organs. EMT is regulated primarily at the transcriptional level by a series of transcription factors (e.g., Twist, Snail, and Zeb1) and miRNAs (e.g., the mir200 family), which coordinately repress epithelial genes and activate mesenchymal genes (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (5278) Google Scholar). Classical features of EMT include the loss of adherens and tight junction components (e.g., E-cadherin, claudins) and the acquisition of chemoresistance and stem-cell-like properties (Ye and Weinberg, 2015Ye X. Weinberg R.A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression.Trends Cell Biol. 2015; 25: 675-686Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar). In practice, however, the biological effects of EMT are intricate and diverse. The EMT-associated traits of a tumor cell may vary depending on the type of tissue and malignancy and the specific EMT signals present. An additional layer of complexity lies in the notion of the “partial EMT” (P-EMT). Instead of acting as a binary switch between fully epithelial and mesenchymal states, EMT programs may generate cells comprising a spectrum of intermediate EMT stages (Grigore et al., 2016Grigore A.D. Jolly M.K. Jia D. Farach-Carson M.C. Levine H. Tumor budding: the name is EMT. Partial EMT.J. Clin. Med. 2016; 5: 51Crossref PubMed Scopus (303) Google Scholar, Pastushenko et al., 2018Pastushenko I. Brisebarre A. Sifrim A. Fioramonti M. Revenco T. Boumahdi S. Van Keymeulen A. Brown D. Moers V. Lemaire S. et al.Identification of the tumour transition states occurring during EMT.Nature. 2018; 556: 463-468Crossref PubMed Scopus (754) Google Scholar). Thus, cells may simultaneously exhibit both epithelial and mesenchymal properties. However, it is unclear whether partial EMT is induced by the same molecular mechanisms that orchestrate classical “complete” EMT, or how the resulting metastatic and invasive characteristics may differ (Aceto et al., 2014Aceto N. Bardia A. Miyamoto D.T. Donaldson M.C. Wittner B.S. Spencer J.A. Yu M. Pely A. Engstrom A. Zhu H. et al.Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis.Cell. 2014; 158: 1110-1122Abstract Full Text Full Text PDF PubMed Scopus (1529) Google Scholar, Cheung et al., 2013Cheung K.J. Gabrielson E. Werb Z. Ewald A.J. Collective invasion in breast cancer requires a conserved basal epithelial program.Cell. 2013; 155: 1639-1651Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar). In this issue of Developmental Cell, two important studies by Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar and Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar shed light on some of these puzzles. Using a mouse model of pancreatic ductal adenocarcinoma (PDAC), Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar investigated the EMT programs employed by tumor cells. Primary tumor cells were first sorted according to their expression of membranous E-cadherin protein into M-ECAD+ (epithelial) and M-ECAD− (mesenchymal) subsets. Through RNA-seq, the authors found that M-ECAD− cells from different tumors can be subdivided into two groups. The first group exhibits reduced mRNA levels of E-cadherin and other epithelial markers, consistent with a complete EMT phenotype. Surprisingly, the second group continues to express E-cadherin mRNA, suggesting that the loss of epithelial proteins occurs post-transcriptionally. This is described as P-EMT. The authors observed that P-EMT cells lacking membranous E-cadherin contain intracellular foci of E-cadherin, which are also positive for Rab11 GTPase, a marker of recycling endocytic vesicles (Figure 1A). These results suggest a distinct partial EMT program that is mediated by protein internalization, in contrast to the conventional view that epithelial plasticity is regulated by changes in gene expression. Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar then asked whether these different EMT programs impacted cell behavior. Indeed they demonstrated that “complete EMT” cells invade their surroundings mostly as single circulating tumor cells (CTCs), whereas tumor cells that undergo P-EMT can invade either as single cells or as collective groups held together by cell-cell adhesion, giving rise to clusters of CTCs. Taken together, this study provides robust evidence that alternative EMT programs exist in cancer cells and dictate the means of cell migration. The study by Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar explored epithelial plasticity in PDAC by manipulating the expression of p120 Catenin (P120CTN), a protein that binds and stabilizes E-cadherin. The authors began with the curious observation that in metastatic PDAC mouse models, mice with intact P120CTN and stabilized E-cadherin predominantly experience liver metastasis; however, genetic abrogation of P120CTN significantly shifts the metastatic burden to the lungs. This striking difference appears to be mediated by the differential epithelial status of the tumor cells. Invasive tumor cells in the primary tumor show EMT characteristics with low E-cadherin expression, but most liver metastatic lesions exhibit robust staining for membranous P120CTN and E-cadherin, suggesting a reversion to epithelial phenotype by MET. By contrast, lung metastases do not express P120CTN or E-cadherin, suggesting epithelial phenotype as an arbiter of metastatic site choice in PDAC. Focusing on the colonization step of metastasis, the authors inoculated different PDAC cell lines varying in P120CTN expression into the liver and lungs. Cells with wild-type or single copy deletion of P120CTN, but not biallelic deletion, are able to form liver metastases. Conversely, PDAC cells can colonize the lungs regardless of their p120CTN expression (Figure 1B). Interestingly, cells that lack P120CTN have a spindle-like shape and upregulate EMT-related genes. Further analysis of human and mouse PDAC RNA-seq datasets demonstrated that genes associated with a “P120CTN low” phenotype are also associated with a mesenchymal signature. The authors conclude that P120CTN status modulates epithelial plasticity and metastatic organotropism in PDAC. Although these two studies use very different approaches to investigate epithelial plasticity in pancreatic cancer, several unifying themes emerge. First, these studies augment a growing body of evidence illuminating epithelial plasticity as a dynamic range of phenotypes, rather than being distinctively epithelial or mesenchymal (Pastushenko et al., 2018Pastushenko I. Brisebarre A. Sifrim A. Fioramonti M. Revenco T. Boumahdi S. Van Keymeulen A. Brown D. Moers V. Lemaire S. et al.Identification of the tumour transition states occurring during EMT.Nature. 2018; 556: 463-468Crossref PubMed Scopus (754) Google Scholar, Ye and Weinberg, 2015Ye X. Weinberg R.A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression.Trends Cell Biol. 2015; 25: 675-686Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar). Moreover, an intermediate EMT state has been proposed to confer greater metastatic capability than the fully mesenchymal state resulting from complete EMT (Li and Kang, 2016Li W. Kang Y. Probing the fifty shades of EMT in metastasis.Trends Cancer. 2016; 2: 65-67Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), perhaps by maintaining plasticity. Consistent with this notion, Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar proposes the compelling idea that a complete loss of P120CTN restricts cells to a fixed mesenchymal status, rendering them unable to colonize the liver. In addition, the partial EMT mechanism uncovered by Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar raises the possibility that internalization of E-cadherin in recycling endosomes may allow their later redistribution to the cell surface. Finding the right balance in EMT appears to be crucial in determining how tumors spread, but further study requires precise manipulation of epithelial status at different stages of metastasis. Both papers also provide insights into how epithelial plasticity impacts cancer dissemination. In Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, only partial EMT tumors, but not those with complete EMT, give rise to CTC clusters. Consistently, Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar observed that single CTCs assume a mesenchymal phenotype, whereas CTC clusters are epithelial-like, strongly suggesting that maintenance of membranous E-cadherin is a prerequisite for cluster formation. With CTC clusters reported to be more efficient at seeding metastases than single cells (Aceto et al., 2014Aceto N. Bardia A. Miyamoto D.T. Donaldson M.C. Wittner B.S. Spencer J.A. Yu M. Pely A. Engstrom A. Zhu H. et al.Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis.Cell. 2014; 158: 1110-1122Abstract Full Text Full Text PDF PubMed Scopus (1529) Google Scholar), it is tempting to speculate that a partial EMT phenotype would be associated with a worse metastatic outcome than complete EMT. However, comprehensive studies are needed to define the epithelial status of matched primary tumors, CTCs, and metastatic lesions and how these affect clinical outcome. Clearly, there is much more to learn about the complex regulatory mechanisms and biological consequences of different types of EMT. Nonetheless, the studies by Aiello et al., 2018Aiello N.M. Maddipati R. Norgard R.J. Balli D. Li J. Yuan S. Yamazoe T. Black T. Sahmoud A. Furth E.E. et al.EMT subtype influences epithelial plasticity and mode of cell migration.Dev. Cell. 2018; 45 (this issue): 681-695Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar and Reichert et al., 2018Reichert M. Bakir B. Moreira L. Pitarresi J.R. Feldmann K. Simon L. Suzuki K. Maddipati R. Rhim A.D. Schlitter A.M. et al.Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer.Dev. Cell. 2018; 45 (this issue): 696-711Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar pave the way for more exciting discoveries in this rapidly evolving field. EMT Subtype Influences Epithelial Plasticity and Mode of Cell MigrationAiello et al.Developmental CellJune 18, 2018In BriefUsing a lineage-traced tumor model, Aiello et al. describe a program of epithelial-to-mesenchymal transition (EMT), conserved across several carcinomas, involving re-localization of epithelial proteins rather than transcriptional repression. This alternative program leads to a “partial EMT” phenotype that promotes collective tumor cell migration and formation of circulating tumor cell clusters. Full-Text PDF Open ArchiveRegulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic CancerReichert et al.Developmental CellJune 18, 2018In BriefThe functional basis of metastatic organotropism sheds light on the properties required for successful colonization of distant organs. Reichert et al. demonstrate that epithelial plasticity is a determinant of metastatic organotropism in pancreatic cancer with differing properties required for liver and lung colonization. Full-Text PDF Open Archive
Referência(s)