Why is downregulation of E-cadherin the hallmark molecular event of EMT?
AE-cadherin is a protease that degrades the basement membrane
BE-cadherin is the primary cell-cell adhesion molecule in epithelial tissues; its loss dissolves adherens junctions, disrupts epithelial integrity, frees cells from their neighbors, and is both necessary and sufficient for the transition from cohesive epithelial behavior to individual migratory behavior
CE-cadherin blocks cell division; its loss allows proliferation
DE-cadherin is a mesenchymal marker that must be removed for epithelial identity
E-cadherin (encoded by CDH1) is the master adhesion molecule of epithelial tissues. It mediates calcium-dependent homophilic cell-cell adhesion at adherens junctions and connects to the actin cytoskeleton through catenins. When EMT transcription factors (Snail, ZEB1/2) repress E-cadherin transcription, the adherens junctions disassemble, the cells lose their connection to neighbors, apical-basal polarity collapses (because polarity complexes are anchored at junctions), and the cells acquire the ability to migrate individually. Re-expression of E-cadherin (during MET) reverses this, restoring adhesion and epithelial character. CDH1 loss is also one of the most common genetic events in invasive lobular breast cancer.
Question 2 True / False
EMT produces a complete, binary switch from epithelial to mesenchymal identity in all biological contexts.
TTrue
FFalse
Answer: False
Recent research has revealed that EMT is often partial, producing cells in intermediate or 'hybrid' states that express both epithelial and mesenchymal markers simultaneously. These partial-EMT states are increasingly recognized as biologically important: in development, migrating cells often retain some cell-cell adhesion (enabling collective migration), and in cancer, partial-EMT cells at the tumor invasive front may be more metastatic than fully mesenchymal cells. EMT is better understood as a spectrum of states rather than a binary switch, with different signaling contexts producing different positions along the epithelial-mesenchymal continuum.
Question 3 Short Answer
How does EMT contribute to cancer metastasis, and why must the reverse process (MET) also occur for successful metastatic colonization?
Think about your answer, then reveal below.
Model answer: EMT enables cancer cells at the primary tumor to lose epithelial adhesion, invade through the basement membrane and surrounding stroma, and enter blood or lymphatic vessels (intravasation). The mesenchymal properties — motility, invasiveness, resistance to anoikis (cell death upon detachment) — are essential for these early metastatic steps. However, at the distant metastatic site, the cells must re-establish epithelial character (MET) to form the cell-cell adhesions and proliferative capacity needed to grow into a macroscopic metastasis. Purely mesenchymal cells are migratory but proliferate slowly; purely epithelial cells proliferate but cannot invade. Successful metastasis requires plasticity — the ability to switch between states as needed for each step of the metastatic cascade.
This requirement for both EMT and MET during metastasis suggests that therapeutic targeting of EMT could be counterproductive if it forces cells into a fully epithelial state at the wrong location — a concern that has complicated anti-EMT drug development. Targeting the plasticity itself (the ability to switch) may be more effective.