EMT/MET Flashcards

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1
Q

Why is EMT/MET a good area to study?

A
  • required for embryonal development
  • can be altered or reactivated in cancer
  • could be a route of treatment
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2
Q

What are the 4 primary tissues?

A
  • muscle
  • connective tissue
  • nerve tissue
  • epithelial tissue
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3
Q

What are the characteristics of epithelial cells? (3)

A
  • usually a single organised layer
  • connected by tight adhesions that prevent migration from the monolayer
  • regularly spaced junctions and adheions between cells
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4
Q

What are the 4 types of junction between epithelial cells?

A
  • tight adhesions control passage of fluids and solutes and maintain cellular polarity by erstricting the movement of membrane proteins and lipids
  • gap junctions direct cell-cell communication
  • adherens junctions - contacts between cells
  • desmosomes - mechanical strength ant stability in tissues under high mechanical pressure such as the skin and heart
  • all allow the movement of nutrients ions and signalling molcules and maintain structure and adhesion
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5
Q

Why is epithelium important / what does it do? (4)

A
  • maintains shape and structure
  • absorption and secretion
  • apical-basal polarity i.e the sides can interact with different molecules and perform different functions
  • first protective layer against pathogens and damage
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6
Q

What are the characteristics of a mesenchymal cell? (5)

A
  • lack of regimented structure
  • stretched and elongated in shape
  • often form irregular compositions and densities
  • fewer tight junctions allow movement from the tissue
  • can migrate and invade the basement membrane
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7
Q

What is EMT?

A
  • epithelial to mesenchymal transition
  • cell-cell and cell-ECM adhesions are lost to allow the cell to come away from the epithelial monolayer
  • cytoskeleton rearrangements allow 3D movement of cells in teh ECM
  • altered genetic program to maintain the new mesenchymal phenotype
  • reversible process
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8
Q

Name 2 changes in cell structure seen in EMT

A
  • from cortical actin to actin stress fibres
  • polarity from apical-basal to front-back
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9
Q

What are the 3 types of EMT?

A
  • development - cycles of EMT and MET involved in producing tissues during development
  • chronic injury - cells undergo EMT to replace damaged cells due to injury - can become chronic
  • malignancy - change in phenotype of tumour cells from epithelial to mesenchymal can allow them to migrate and metastasise
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10
Q

Describe one of the first EMTs in development

A
  • production of the germ layers
  • ectoderm - mesoderm EMT
  • mesoderm - endoderm MET
  • neural crest cells undergo MET to migrate around the body and form neurons
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11
Q

Give some examples of cells derived from mesoderm EMT and neural crest EMT

A
  • mesoderm produces bone, muscles and blood
  • neural crest produces neurons, glial cells and skeletal muscle
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12
Q

What signalling occurs in embryonic EMT gastrulation signalling?

A
  • leads to mesoderm ingression
  • TGF-B and nodal -> SMAD, slug snail and twist (downregulate e-cadherin and upregulate n-cadherin and other mesenchymal markers)
  • Wnt -> B-catenin can also modulate these genes
  • FGF activates MAPK/ERK and movement
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13
Q

What signalling occurs in embyronic EMT neural crest development?

A
  • Wnt, notch and FGF
  • notch involved in determining cell fate
  • trigger enzymes and TFs such as sox9
  • signalling cascade leading to neural crest delamination
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14
Q

How does Wnt act in EMT? as an example

A
  • wnt can cause B-catenin to enter the nucleus and begin the transcription of SNAIL1/2 or activate other genes in EMT
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15
Q

How do inflammation and hypoxia lead to emt?

A

inflammation can signal STAT3 and cause EMT
hypoxia can signal Hif1-alpha and cause EMT

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16
Q

EMT and MET are essential in development. They are hyjacked in cancer and implicated in:

A
  • cancer dissemination
  • cancer initiation
  • metastasis
  • drug resistance
  • CSC generation
17
Q

What kind of signals might trigger EMT in cancer? (5)

A
  • physical constrains
  • hypoxia
  • inflammation
  • oncogenic stress
  • metaboolic stress
18
Q

Name 4 signalling pathways seen in EMT

A
  • Wnt
  • Notch
  • Hif1/2
  • TGF-B
19
Q

Name 3 TFs involved in EMT

A
  • SNAIL 1/2
  • TWIST 1/2 seen mutated in colon cancer
  • ZEB1/2 seen mutated in pancreatic cancer
20
Q

How generally might EMT TFs cause primary lesions and invasion?

A
  • might inhibit p53/Rb and alter differentiation and stemness
  • may inhibit cell polarity and cell-cell contacts to allow migration
21
Q

What are the roles of EMT/MET in normal adult tissue?

A
  • wound healing
  • hypothesised to be the way adult stem cells are created
22
Q

Name 5 roles of EMT/MET in cancer progression

A
  • cancer initiation
  • cancer dissemination
  • metastasis
  • CSC generation
  • drug resistance
23
Q

How is EMT/MET involved in cancer dissemination?

A
  • EMT
  • early in cancer development cells can undergo EMT and enter the blood stream
  • travel to other parts of the body and remain dormant there
24
Q

How is EMT/MET involved in cancer initiation?

A
  • EMT
  • cancer cells need to interact with stromal cells such as fibroblasts and immune cells
  • cells need to break through and invade the basement membrane to do so and so need a mesenchymal phenotype
25
Q

How is EMT/MET involved in cancer metastasis?

A
  • tumour cells undergo EMT to break away from the tissue and enter the blood stream
  • when they reach secondary sites, they can undergo MET to settle at new organs and form secondary tumours
26
Q

How are EMT/MET involved in cancer stem cell generation?

A
  • cells can undergo partial EMT
  • can enter a stemness window where they have the properties of a stem cell
  • quasiepithelial/quasimesenchymal cells can migrate, invade and devide at distant sites
  • express genes to maintain stemness such as Oct4
27
Q

How do cancer stem cells contribute to chemoresistance?

A
  • many cancer cells are receptive to epigenetic treatments such as HDACs to silence oncogene activity
  • when cells undergo partial EMT they develop new surface molecules and phenotypes that treatments don’t work on
  • treatment needs to get rid of cancer stem cells or cancer will always return
28
Q

What occurs in regards to EMT/MET to cause Wilm’s tumour?

A
  • failure of mesenchymal differentiation (MET)
  • tumours ressemble developing kidney structures and stroma
  • due to WT1 gene imprinting failure
29
Q

How can miRNAs regulate EMT-MET?

A

-transcriptional regulators act in feedback loops with miRNAs
- let-7 is essential for development and inhibits RAS and other oncogenes in MET
- epigenetic regulators such as polycomb proteins also interact with miR-200 and E-cadehin in feedback loops.

30
Q

What is the role of E-cadherin?

A

maintenance of epithelial phenotype - suppresses EMT

31
Q

What is the role of B-catenin?

A

regulation of EMT genes to turn them on (Wnt)