Epithelial–mesenchymal transition (EMT) is a process in which epithelial cells acquire mesenchymal features. In cancer, EMT is associated with tumor initiation, invasion, metastasis, and resistance ...to therapy. Recently, it has been demonstrated that EMT is not a binary process, but occurs through distinct cellular states. Here, we review the recent studies that demonstrate the existence of these different EMT states in cancer and the mechanisms regulating their functions. We discuss the different functional characteristics, such as proliferation, propagation, plasticity, invasion, and metastasis associated with the distinct EMT states. We summarize the role of the transcriptional and epigenetic landscapes, gene regulatory network and their surrounding niche in controlling the transition through the different EMT states.
EMT occurs through distinct intermediate states in vivo.
Distinct EMT transition states can be identified using cell surface markers and single-cell RNA-sequencing.
Distinct EMT transition states present different functions, with the hybrid EMT state presenting the highest metastatic potential.
Distinct EMT transition states present different gene expression and chromatin landscape.
Distinct EMT transition states are localized in different niches that regulate cell fate transitions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Our traditional understanding of phenotypic plasticity in adult somatic cells comprises dedifferentiation and transdifferentiation in the context of tissue regeneration or wound healing. Although ...dedifferentiation is central to tissue repair and stemness, this process inherently carries the risk of cancer initiation. Consequently, recent research suggests phenotypic plasticity as a new paradigm for understanding cancer initiation, progression, and resistance to therapy. Here, we discuss how cells acquire plasticity and the role of plasticity in initiating cancer, cancer progression, and metastasis and in developing therapy resistance. We also highlight the epithelial-to-mesenchymal transition (EMT) and known molecular mechanisms underlying plasticity and we consider potential therapeutic avenues.
Gupta et al. discuss how cells acquire plasticity and the role of plasticity in initiating cancer, cancer progression, and metastasis and in developing therapy resistance. The article also highlights the epithelial-to-mesenchymal transition (EMT) and known molecular mechanisms underlying plasticity, and it considers potential therapeutic avenues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epithelial-to-mesenchymal transition (EMT) has been proposed to be important for metastatic dissemination. However, recent studies have challenged the requirement of EMT for metastasis. Here, we ...assessed in different models of primary skin squamous cell carcinomas (SCCs) whether EMT is associated with metastasis. The incidence of metastasis was much higher in SCCs presenting EMT compared to SCCs without EMT, supporting the notion that a certain degree of EMT is required to initiate the metastatic cascade in primary skin SCCs. Most circulating tumor cells presented EMT, whereas most lung metastasis did not present EMT, showing that mesenchymal-to-epithelial transition is important for metastatic colonization. In contrast, immunodeficient mice transplanted with SCCs, whether displaying EMT or not, presented metastasis. Altogether, our data demonstrate that the association of EMT and metastasis is model dependent, and metastasis of primary skin SCCs is associated with EMT.
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•Primary skin SCCs with EMT have a high incidence of metastasis•Primary skin SCCs without EMT have no metastasis•Circulating tumor cells present EMT in primary tumors with metastasis•Transplanted tumors present metastasis regardless of EMT
The role of epithelial-to-mesenchymal transition (EMT) during metastasis remains controversial. Revenco et al. show that in models of primary skin tumors, only EMT tumors are associated with metastasis. In contrast, EMT is not required to induce metastasis following the subcutaneous transplantation of tumor cells, demonstrating the context dependency of EMT for metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In cancer biology, epithelial-to-mesenchymal transition (EMT) is associated with tumorigenesis, stemness, invasion, metastasis, and resistance to therapy. Evidence of co-expression of epithelial and ...mesenchymal markers suggests that EMT should be a stepwise process with distinct intermediate states rather than a binary switch. In the present study, we propose a morphological approach that enables the detection and quantification of cancer cells with hybrid E/M states, i.e., which combine partially epithelial (E) and partially mesenchymal (M) states. This approach is based on a sequential immunohistochemistry technique performed on the same tissue section, the digitization of whole slides, and image processing. The aim is to extract quantitative indicators able to quantify the presence of hybrid E/M states in large series of human cancer samples and to analyze their relationship with cancer aggressiveness. As a proof of concept, we applied our methodology to a series of about a hundred urothelial carcinomas and demonstrated that the presence of cancer cells with hybrid E/M phenotypes at the time of diagnosis is strongly associated with a poor prognostic value, independently of standard clinicopathological features. Although validation on a larger case series and other cancer types is required, our data support the hybrid E/M score as a promising prognostic biomarker for carcinoma patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The utility of human neuroblastoma cell lines as in vitro model to study neuro-invasiveness and neuro-virulence of SARS-CoV-2 has been demonstrated by our laboratory and others. The aim of this ...report is to further characterize the associated cellular responses caused by a pre-alpha SARS-CoV-2 strain on differentiated SH-SY5Y and to prevent its cytopathic effect by using a set of entry inhibitors. The susceptibility of SH-SY5Y to SARS-CoV-2 was confirmed at high multiplicity-of-infection, without viral replication or release. Infection caused a reduction in the length of neuritic processes, occurrence of plasma membrane blebs, cell clustering, and changes in lipid droplets electron density. No changes in the expression of cytoskeletal proteins, such as tubulins or tau, could explain neurite shortening. To counteract the toxic effect on neurites, entry inhibitors targeting TMPRSS2, ACE2, NRP1 receptors, and Spike RBD were co-incubated with the viral inoculum. The neurite shortening could be prevented by the highest concentration of camostat mesylate, anti-RBD antibody, and NRP1 inhibitor, but not by soluble ACE2. According to the degree of entry inhibition, the average amount of intracellular viral RNA was negatively correlated to neurite length. This study demonstrated that targeting specific SARS-CoV-2 host receptors could reverse its neurocytopathic effect on SH-SY5Y.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Within a tumor, cancer cells exist in different states that are associated with distinct tumor functions, including proliferation, differentiation, invasion, metastasis, and resistance to anti‐cancer ...therapy. The identification of the gene regulatory networks underpinning each state is essential for better understanding functional tumor heterogeneity and revealing tumor vulnerabilities. Here, we review the different studies identifying tumor states by single‐cell sequencing approaches and the mechanisms that promote and sustain these functional states and regulate their transitions. We also describe how different tumor states are spatially distributed and interact with the specific stromal cells that compose the tumor microenvironment. Finally, we discuss how the understanding of tumor plasticity and transition states can be used to develop new strategies to improve cancer therapy.
The mechanisms instructing functionally distinct tumor states and their transitions during tumor progression, metastasis, and response to therapy analysed by single‐cell methodologies are reviewed here.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In cancer, the epithelial-to-mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary ...process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here we screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour-propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.
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KISLJ, NUK, SBMB, UL, UM, UPUK
FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers
. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation ...and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
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KISLJ, NUK, SBMB, UL, UM, UPUK
Abstract
Epithelial to Mesenchymal Transition (EMT), rather than being a binary switch, has been hypothesized to represent a spectrum of intermediate tumor states, but direct evidence supporting this ...concept in vivo in primary tumors is still lacking. In addition, the number of distinct states and the mechanisms regulating the transition between them, their plasticity, and their implication in tumor progression and metastasis are hitherto unknown.
Here, we used a genetic mouse model of skin squamous cell carcinoma mediated by oncogenic KRasG12D and p53 loss of function that undergoes spontaneous EMT to identify different subpopulations of epithelial (Epcam+) and mesenchymal (Epcam-) tumor cells. To this end, we screened a large panel (>250) of cell surface markers, uncovering 15 markers that were heterogeneously expressed during EMT. Using multicolour FACS analysis we identified up to 6 different tumor subpopulations representing the different EMT transitional states that occurred spontaneously during tumorigenesis in vivo. Cytospin using K14 and Vimentin as well as qRT-PCR with well-characterized markers of epithelial and mesenchymal states confirmed that these different populations represent EMT transitional states, from very early hybrid epithelial/mesenchymal states to completely mesenchymal states. Transplantation of limiting dilution of these
different populations into immunodeficient mice showed that they exhibit similar tumor propagating cell frequency. However, phenotypic analysis of the secondary tumors revealed that these populations present different plasticity with the populations characterized by the early steps of EMT giving rise preferentially to tumors with epithelial features whereas the tumor cell populations corresponding to the late stages of EMT preferentially giving rise to tumors with mesenchymal features, identifying the point of no return during EMT. To determine the molecular mechanism controlling these cell state transitions, we assessed their transcriptional and epigenetic landscapes using RNA-seq and ATAC-seq. We uncovered transcription factors (TFs) and signaling pathways specifically enriched in the different tumor subpopulations. Additional functional experiments using CRISPR-Cas9 deletion of the newly identified TFs, as well as the ligands identified the key molecular features that stimulate the different transition states during EMT. Finally, we found that the distinct populations of tumor cells exhibit great differences in metastatic frequency and identified the tumor cell population with highest metastatic potential, opening new avenues for therapy.
Altogether our findings identified for the first time the different transitional states associated with EMT in primary tumors in vivo and uncovered the molecular mechanisms associated with these transition states, as well as their importance for metastasis.
Citation Format: Ievgenia Pastushenko, Panagiota Sotiropoulou, Cédric Blanpain. Identification of the tumor transition states occurring during EMT and their implications for metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-146. doi:10.1158/1538-7445.AM2017-LB-146
Background
Onychomycosis affects 5.5% of the general population and represents up to 50% of all nail diseases. Diagnosis and pathogen identification are essential in order to plan an adequate ...treatment. Many diagnostic techniques are available, and however, no solid data regarding comparison between different techniques over a large number of specimens are available to date.
Objectives
To compare sensitivity and specificity of direct examination, histopathology and fungal culture in our referral mycology laboratory.
Methods
Nail specimens received at the cutaneous pathology and mycology laboratory of the University Hospital Saint‐Pierre (Brussels, Belgium) between 1 January and 15 May 2018 were retrospectively analysed. All specimens were submitted to direct examination and culture. In cases of adequate specimen size, histopathology was performed. Fungal culture was considered the gold standard for diagnosis.
Results
A total of 2245 nail samples were included in the study. Onychomycosis was diagnosed in 1266 specimens. Sensitivity and positive predictive value were found to be higher for direct examination compared to histopathology, while sensitivity of direct examination was found to be lower. Combined approach with all the three techniques showed the highest rate of positivity, followed by the association of direct examination and histopathology.
Conclusions
To our knowledge, this study included the largest number of nail specimens to date, allowing a comparison between direct examination, culture and histopathology. Direct examination showed to be the most performing technique in routine practice. Histopathology represents the most effective option in cases where both specimen size and laboratory resources are adequate. Our paper adds to the literature the ‘real‐life’ experience of the mycology laboratory of a referral centre for nail diseases.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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