Epithelial-Mesenchymal Transition (EMT)

• EMT stands for epithelial-mesenchymal transition
• EMT is a biological process that allows polarized epithelial cells to undergo transition to mesenchymal cells
• This involves biochemical changes
• EMT programs are activated during:
  • Embryonic development
  • Wound healing
  • Cancer progression

Characteristics of EMT

• EMT is characterized by a loss of epithelial cell polarity and cell-cell adhesion
• EMT is characterized by increased migratory capacity
• EMT is characterized by increased invasiveness
• EMT is characterized by elevated resistance to apoptosis

Molecular Changes During EMT

• Downregulation of E-cadherin is a hallmark of EMT
  • E-cadherin is a cell adhesion molecule crucial for maintaining epithelial cell junctions
• Upregulation of mesenchymal markers such as vimentin, N-cadherin, fibronectin, and transcription factors like Snail, Slug, Twist, and Zeb occurs
• These transcription factors repress epithelial genes and activate mesenchymal genes

Types of EMT

• There are three subtypes of EMT:
  • Type 1 EMT
  • Type 2 EMT
  • Type 3 EMT
• These subtypes are defined based on the biological context in which they occur

Type 1 EMT

• Occurs during embryonic development
• Is crucial for the formation of various tissues and organs
• Involves the migration of cells to form new structures
• After development, cells undergo the reverse process (MET - mesenchymal-epithelial transition) to establish tissue architecture

Type 2 EMT

• Is associated with wound healing, tissue regeneration, and organ fibrosis
• Following tissue damage, epithelial cells undergo EMT to migrate to the site of injury and contribute to tissue repair
• Prolonged or dysregulated Type 2 EMT can lead to fibrosis, where excessive deposition of extracellular matrix results in tissue scarring and organ dysfunction

Type 3 EMT

• Is associated with cancer progression and metastasis
• Cancer cells undergo EMT to detach from the primary tumor, invade surrounding tissues, enter the bloodstream, and colonize distant sites
• EMT in cancer promotes drug resistance and immune evasion

Signaling Pathways Involved in EMT

• Several signaling pathways regulate EMT, including:
  • TGF-β (transforming growth factor-beta)
  • Wnt
  • Notch
  • Hedgehog
  • Receptor tyrosine kinases (RTKs)
• These pathways activate transcription factors that drive EMT

TGF-β Signaling

• TGF-β is a potent inducer of EMT
• TGF-β activates Smad proteins, which translocate to the nucleus and regulate the expression of EMT-related genes
• TGF-β can also activate non-Smad pathways, such as MAPK and PI3K, to promote EMT

Wnt Signaling

• Wnt signaling is involved in embryonic development and cancer
• Activation of Wnt signaling leads to the accumulation of β-catenin in the cytoplasm
• β-catenin translocates to the nucleus and activates the transcription of target genes, including EMT-inducing transcription factors

Notch Signaling

• Notch signaling plays a role in cell fate determination and EMT
• Activation of Notch receptors leads to the release of the Notch intracellular domain (NICD)
• NICD translocates to the nucleus and regulates the expression of target genes involved in EMT

EMT and Cancer Metastasis

• EMT plays a critical role in cancer metastasis
• EMT enables cancer cells to detach from the primary tumor, invade surrounding tissues, and enter the bloodstream
• Circulating tumor cells (CTCs) can then colonize distant organs, leading to the formation of secondary tumors
• Not all cancer cells undergo full EMT; some may undergo partial EMT, which still promotes metastasis

Therapeutic Targeting of EMT

• Targeting EMT is a promising strategy for cancer therapy
• Several approaches are being developed to inhibit EMT, including:
  • Blocking EMT-inducing signaling pathways
  • Inhibiting EMT-related transcription factors
  • Restoring epithelial characteristics in cancer cells
• EMT inhibitors are being tested in preclinical and clinical studies

EMT and Drug Resistance

• EMT can contribute to drug resistance in cancer cells
• Mesenchymal cells are often more resistant to chemotherapy and targeted therapies compared to epithelial cells
• EMT can promote the expression of drug efflux pumps, which pump drugs out of cancer cells
• EMT can induce changes in cell metabolism that reduce the sensitivity to certain drugs

EMT and Immune Evasion

• EMT can promote immune evasion in cancer cells
• Mesenchymal cells may express lower levels of MHC class I molecules, making them less susceptible to T cell-mediated killing
• EMT can induce the expression of immunosuppressive factors, such as PD-L1, which inhibit immune cell activity
• EMT can also promote the recruitment of immunosuppressive cells, such as regulatory T cells (Tregs), to the tumor microenvironment

EMT in Fibrosis

• EMT is implicated in the pathogenesis of organ fibrosis
• During fibrosis, epithelial cells in the affected organ undergo EMT and contribute to the excessive deposition of extracellular matrix
• Myofibroblasts, the primary effector cells in fibrosis, can originate from epithelial cells via EMT
• EMT inhibitors are being investigated as potential therapies for fibrotic diseases

EMT and Stemness

• EMT is associated with the acquisition of stem cell-like properties in cancer cells
• Cancer cells that have undergone EMT often exhibit increased self-renewal capacity and the ability to differentiate into multiple cell types
• EMT-induced stemness can promote tumor initiation, metastasis, and drug resistance

Challenges in EMT Research

• Studying EMT is challenging due to its dynamic and context-dependent nature
• EMT is not an all-or-nothing process; cells can exist in intermediate states between epithelial and mesenchymal phenotypes
• The markers used to define EMT can vary depending on the cell type and context
• There is a need for better tools and methods to study EMT in vivo and in vitro

Future Directions in EMT Research

• Future research directions in EMT include:
  • Identifying novel EMT regulators and targets
  • Developing more specific and effective EMT inhibitors
  • Understanding the role of EMT in different stages of cancer progression
  • Investigating the interplay between EMT and the tumor microenvironment
  • Developing biomarkers to predict EMT and response to therapy
• A better understanding of EMT will lead to improved strategies for the treatment and prevention of cancer and other diseases

Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells transform into mesenchymal cells. This transition involves biochemical changes and is activated during embryonic development, wound healing, and cancer progression. EMT is marked by loss of cell polarity, increased migration, invasiveness, and apoptosis resistance.