Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT

Abstract

Epithelial to mesenchymal transition (EMT) is a critical cellular process that has been well characterized during embryonic development and cancer metastasis and it also is implicated in several physiological and pathological events including embryonic stem cell differentiation. During early stages of differentiation, human embryonic stem cells pass through EMT where deeper morphological, molecular and biochemical changes occur. Though initially considered as a decision between two states, EMT process is now regarded as a fluid transition where cells exist on a spectrum of intermediate states. In this work, using a CRISPR interference system in human embryonic stem cells, we describe a molecular characterization of the effects of downregulation of E-cadherin, one of the main initiation events of EMT, as a unique start signal. Our results suggest that the decrease and delocalization of E-cadherin causes an incomplete EMT where cells retain their undifferentiated state while expressing several characteristics of a mesenchymal-like phenotype. Namely, we found that E-cadherin downregulation induces SNAI1 and SNAI2 upregulation, promotes MALAT1 and LINC-ROR downregulation, modulates the expression of tight junction occludin 1 and gap junction connexin 43, increases human embryonic stem cells migratory capacity and delocalize bcatenin. Altogether, we believe our results provide a useful tool to model the molecular events of an unstable intermediate state and further identify multiple layers of molecular changes that occur during partial EMT. E-cadherin | Pluripotent Stem Cells | Partial EMTCorrespondence: cluzzani@fleni.org.ar

Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts

“…This concordance suggests an overlap of core expression patterns central to EMT in a highdimensional feature space and indicates that these metrics -initially developed for cancer samples -can be applied more generally to a broader range of biological contexts. Using these metrics in biological contexts where hybrid E/M states have been proposed (Aban et al, 2020;Grande et al, 2015;Jolly et al, 2018) may be helpful in mapping the corresponding trajectories of EMT/MET. The hybrid E/M state has been previously documented at both bulk and single-cell levels during various stages of development as well (Dong et al, 2018;Leroy and Mostov, 2007); here, we have shown proof-of-principle that these scoring metrics can successfully quantify the extent of EMP in mouse models.…”

Regulation of Partial and Reversible Endothelial-to-Mesenchymal Transition in Angiogenesis

“…However, more sophisticated studies have now refuted that idea, and instead support an alternative model wherein most cell fate changes -including both EMT and EndoMT -involve progressive transition from one cell identity to another via a fluid spectrum of intermediate cell states (Lamouille et al, 2014;Sha et al, 2019). In support of this latter model, initiation of EMT in pluripotent epithelial stem cells through downregulation of the adherens junction protein E-cadherin triggers expression of Slug and related transcription factors, leading to the acquisition of some mesenchymal characteristics; yet, these cells still retain expression of epithelial stem cell markers indicating only a partial EMT (Aban et al, 2021).…”

Molecular pathogenesis and emerging targets of gastric adenocarcinoma

“…44,45 E-cadherin also plays an important role in maintaining cell adhesion and polarity and when mutated, there is a loss of contact inhibition and cell migration. 46,47 Hereditary nonpolyposis colon cancer syndrome is another autosomal dominant disorder associated with an increased risk of GC. This disease is characterized by a mutation in the DNA repair system (MLH1, MSH2, MSH6, PMS2, etc.)…”

“…When E‐cadherin is mutated, it was found that Wnt signaling regulates both proliferation and chemotherapy resistance in GC 44,45 . E‐cadherin also plays an important role in maintaining cell adhesion and polarity and when mutated, there is a loss of contact inhibition and cell migration 46,47 . Hereditary nonpolyposis colon cancer syndrome is another autosomal dominant disorder associated with an increased risk of GC.…”