EMT genes regulate Epithelial-Mesenchymal Transition (EMT), a fundamental biological process. EMT involves a temporary and reversible shift in cell characteristics, allowing cells to change their form and function. These genes orchestrate molecular changes that enable cells to transition from a stationary, connected state to a migratory, invasive one.
The regulation by EMT genes ensures cells can adapt their behavior, which is utilized across different scales of biology, from tissue sculpting during development to the body’s response to injury. Understanding these genes provides insight into how cells acquire new properties, influencing both healthy physiological functions and the progression of certain diseases.
Understanding Epithelial-Mesenchymal Transition
Epithelial-Mesenchymal Transition (EMT) is a biological process where epithelial cells undergo a series of changes to become mesenchymal cells. Epithelial cells typically form cohesive sheets, tightly bound together with distinct top (apical) and bottom (basal) surfaces. They are characterized by strong cell-cell adhesion, maintained by proteins like E-cadherin, and a defined polarity.
Mesenchymal cells, in contrast, are spindle-shaped, less adherent, and possess enhanced migratory and invasive capabilities. During EMT, epithelial cells lose their cell-cell junctions, such as adherens junctions and desmosomes, and their apical-basal polarity.
This transformation also involves a reorganization of the cell’s internal scaffolding, known as the cytoskeleton. The cells experience changes in gene expression, leading to a reduction in epithelial markers like E-cadherin and an increase in mesenchymal markers such as N-cadherin, vimentin, and fibronectin. These molecular and structural alterations allow the cells to detach from their original location, move through tissues, and sometimes differentiate into various cell types.
EMT Genes in Healthy Physiology
EMT genes play a beneficial role in numerous normal biological processes, where their activation is transient and tightly controlled. In embryonic development, EMT is involved in the formation of many tissues and organs. During gastrulation, epiblast cells undergo EMT to migrate and form the three primary germ layers: the ectoderm, mesoderm, and endoderm.
Neural crest cells, which are multipotent cells that differentiate into a wide array of cell types, are also generated through EMT from the neuroectoderm during embryonic development. These cells then dissociate from neural folds, gain motility, and disperse throughout the embryo to form diverse structures, including melanocytes.
EMT genes are also active in wound healing, enabling tissue repair and regeneration after injury. During this process, epithelial cells at the edge of a wound undergo EMT, acquiring migratory properties that allow them to move and cover the damaged area. This temporary change in cell behavior is regulated by various factors, including growth factors like TGF-β, EGF, and FGF, which induce the expression of EMT-promoting transcription factors such as Snail, Slug, Zeb1, Zeb2, and Twist. Once the wound is closed and inflammation subsides, these cells can revert to their epithelial state through a reverse process called mesenchymal-epithelial transition (MET).
EMT Genes and Disease Progression
While EMT is a natural process in healthy development and healing, its dysregulation can contribute to the progression of various diseases. Aberrant EMT gene activity is implicated in cancer metastasis, the spread of cancer cells from a primary tumor to distant sites in the body. Cancer cells hijack the EMT program, losing their cell-cell adhesion and acquiring the migratory and invasive characteristics of mesenchymal cells.
This phenotypic shift allows cancer cells to detach from the primary tumor, break through the surrounding tissue barriers, and enter the bloodstream or lymphatic vessels in a process called intravasation. Once in circulation, these motile cancer cells can travel to distant organs. Upon reaching a new site, they undergo a reverse process, Mesenchymal-Epithelial Transition (MET), to regain epithelial characteristics, which aids in their ability to settle and form new secondary tumors. The activation of EMT in cancer is mediated by various signaling pathways, including WNT, TGF-β, NOTCH, and Hedgehog, which activate EMT-related transcription factors like SNAIL, SLUG, ZEB1/2, or TWIST.
Beyond cancer, dysregulated EMT also contributes to organ fibrosis, a condition characterized by excessive accumulation of extracellular matrix proteins, leading to scarring and impaired organ function. In fibrotic diseases affecting organs such as the lungs, kidneys, and liver, epithelial cells respond to chronic inflammation or injury by undergoing a sustained EMT. This leads to the transformation of epithelial cells into myofibroblasts, which overproduce collagen and other extracellular matrix components, resulting in the stiffening and dysfunction of the affected organ.