EPITHELIAL MESENCHYMAL TRANSITION

Question 1

General introduction about EMT

Answer 1

What EMT is? Biological process which confers a mesenchymal phenotype to epithelial cells through morpho-functional changes, involved in embryonic development, tissue repair and wound healing, organ fibrosis and cancer progression
Concept of transition: phenotypic plasticity and reverse process, MET

Question 2

Classification of EMT

Answer 2

Type I EMT: embryo development and pathways that are involved
Type II EMT: function in tissue repair following a trauma or an injury but also in organ fibrosis, role of the inflammation and of TGF-beta (studies with BMP-7)
Type III EMT: cancer progression and acquisition of the invasiveness and malignant phenotype and phases of tumour development and progression

Question 3

Key steps in EMT

Answer 3

-deconstruction of the cell-junctions and cell polarity
-cytoskeleton rearrangement
-changes in gene expression profile
-activation of transcription factors and regulatory factors
-TGF-beta signalling
-other pathways involved

Question 4

Cancer stem cells

Answer 4

Shift from the stochastic model to the cancer stem cells model
Indentification of the first cancer stem cells in acute myeloid leukemia (CD34+CD38-)
Identification of cancer stem cells in solid tumours (firstly in breast cancer, CD44+CD24- cells)
Common scenario for their study

Question 5

Technological challenges of cancer stem cells

Answer 5

Three questions:
-is the CSC a stable trait?
-how good is the xenograft assay?
-which are bona fide markers? Other methods to identify CSCs (mandatory)

Question 6

Melanoma case of cancer stem cells

Answer 6

Underestimation of the frequency of the cancer stem cells because of the presence of NK cells in the NOD/SCID mouse models.
Re-evaluation in IL-2R-gamma deficient NOD/SCID mice: 28% of individual melanoma cells able to give rise to the tumour of origin in the mouse models > in opposition with the CSC model
New concept: focusing on the histone demethylase JARIB1b > dynamic stemness from non-CSC to CSC, plasticity of the stemness
Complexity: plasticity acquired during therapies to escape and survive

Question 7

Cancer stem cells as target in therapies

Answer 7

Three kinds of approaches:
1) target directly the CSC
2) induce the CSC in a quiescent state to enter into the cell cycle becoming proliferating cells (sensitive to the normal chemotherapy drugs)
3) attack the CSC niche: ex. bevacizumab