Cancer biology teaching at ISI

1. 1
Arpita Banerjee
Cancer Biology
27th September 2020
Indian Statistical Institute, Kolkata

2. Cell
https://www.dreamstime.com/royalty-free-stock-photos-human-cell-image27673358
Cell’s machinery is run by proteins
Arpita Banerjee

3. Cell signalling
https://biologydictionary.net/cell-signaling/ Glycosylation, myristoylation,
phosphorylation etc. are
involved in signalling.
Signal molecule
Receptor
Cellular response(s):
Cell Division
Gene transcription
Protein trafficking
Cell-cell interaction
Cell death
etc.
Downstream
signalling
Arpita Banerjee

4. Intracellular proteins
Extracellular proteins embedded in
plasma membrane of cell could act as
receptors for binding an external signal
molecule for downstream signalling
cascade.
Proteins are molecular machines that run the cell’s machinery
Protein modifications are an important component of function execution
Cell1
Arpita Banerjee
Intracellular proteins
Cell2
Protein modification (say glycosylation)
on an extracellular protein of cell could
act as a signalling molecule for binding
receptors on other proteins to initiate a
biological process

5. Some types of protein modifications
Carbohydrate moiety
Glycosylated protein
Myristoylated protein
Myristic acid
Phosphate group
Phosphorylated protein
Cell
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http://www.phschool.com/science/
biology_place/biocoach/bioprop/folding.html

6. https://en.wikipedia.org/wiki/Myristoylation
https://www.researchgate.net/figure/The-two-major-types-of-protein-glycosylation
https://www.open.edu/openlearn/science-maths-technology/science/biology/proteins
Myristoylation at G-{EDRKHPFYW}-x(2)-[STAGCN]-{P} etc.
Phosphorylation at [RK]-x(2)-[DE]-x(3)-Y etc.
Glycosylation at N-{P}-[ST]-{P} etc.
Modifications at specific sites on protein
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7. Mutations
that immensely affect cell signalling will impact cellular response
that could eventually contribute to cancer progression
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8. Cell division goes awry and other pathways get eventually affected in cancer
Source of damage:
ionizing radiation,
carcinogen, (genetic
predisposition) etc.
Mutations accumulated
Rapid multiplication Normal multiplication
Tumorous cell mass Healthy cells
Further mutations get accumulated
along the way for tumor growth and
invasion into other tissues
Normal Cell
Damaged Cell
Arpita Banerjee

9. 9
Mutations
affecting the protein modification sites
could contribute to cancer progression
Arpita Banerjee

10. Cell signalling
https://biologydictionary.net/cell-signaling/ Glycosylation, myristoylation,
phosphorylation etc. are
involved in signalling.
Signal molecule
Receptor
Cellular response(s):
Cell Division
Gene transcription
Protein trafficking
Cell-cell interaction
Cell death
etc.
Downstream
signalling
Arpita Banerjee

11. What is the cellular process for invasion?
Several coordinated intra and extra cellular
processes
Arpita Banerjee

12. https://www.slideshare.net/VaanikaKaira/neoplasiamolecular-basis-of-cancer
Arpita Banerjee

13. ECM
Initial decoupling from
tumorous tissue.
Docking onto Extra Cellular
Matrix (ECM)
Restructuring of ECM and
invasion into normal brain
tissue.
Cancerous tissue Normal tissue
Simplified representation
Arpita Banerjee

14. Overview of the invasion process highlighting
the roles of some glycosylated proteins
Arpita Banerjee

15. Initial decoupling from tumorous tissue.
Step 1
Cancerous tissue
Decoupled mass
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16. E-Cadherin
Cancer cell
ECM
Cancer cell
E-cadherin aids in holding cells
together, and they also connect
with the ECM
Disruption in E-cadherin mediated
cell-cell attachment
ECM
Cancer cell
Cancer cell
Decoupling of cancer cells from tumorous mass initiates
Initial decoupling from tumorous tissue.
Step 1
Arpita Banerjee

17. Glycosylation plays an important role
Under conditions of stress
Aberrantly
O-glycosylated
O-glycosylation of the cytosolic tail (blue)
of E-cadherin prevents its transport to
plasma memebrane – thereby inactivating
intercellular adhesion
Non-functional E-cadherin due to missing tail
Aberrantly
N-glycosylated
Under conditions of cancer
Non functional E-cadherin due to
lack of cis dimer formation
N-glycosylation of N554 in the
extracellular domain (green) of
E-cadherin prevents cis-dimerization
which in turn impacts trans-dimerization
with E-cadherin of another cell thereby
inactivating intercellular adhesion
Initial decoupling from tumorous tissue.
Step 1
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18. Docking
Docking onto Extra Cellular Matrix (ECM)
Step 2
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19. Cancer cell
CD44
Receptor
ECM cell
Ligand - Hyaluronic acid
Derived from carbohydrate moiety
CD44
Downstream signalling in ECM cell via hyaluronic acid,
aids in progression to step 3 – restructuring of ECM
Docking onto Extra Cellular Matrix (ECM) component (say integrin)
Step 2
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Docked

20. Glycosylation plays an important role
CD44
Hyaluronic acid
(ligand)
Glycosylation
Interaction affected
CD44
Docking onto Extra Cellular Matrix (ECM)
Step 2
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Glycosylation of CD44:
Pattern 1 Docked
Glycosylation of CD44:
Pattern 2 Not docked

21. Glycosylation of CD44:
Pattern 1
Glycosylation of CD44:
Pattern 2
Balance determines attachment of cells to ECM
Docking onto Extra Cellular Matrix (ECM)
Step 2
Arpita Banerjee

22. Glycosylation of CD44:
Pattern 2
Glycosylation of CD44:
Pattern 1
Determines attachment of cancer cells to ECM
Determines invasiveness of cancer cells
Mutations
Docking onto Extra Cellular Matrix (ECM)
Step 2
Arpita Banerjee
If/when mutation(s) shifts the balance shifted towards pattern1

23. CD44
Restructuring of ECM which could
facilitate invasion of cancer cells
into normal tissue.
Restructuring of ECM and invasion into normal brain tissue.
Restructuring of
ECM
Invasion into
normal tissue
Step 3
CD44
ECM
ECM
Arpita Banerjee

24. Restructuring of ECM and invasion into normal tissue.
Step 3
Glycosylation plays an important role
Restructuring essentially involves - ‘breaking and making’.
!
• Proteases play a crucial role in ‘breaking’ the ECM components because of their protein
degrading capability – thereby aiding in restructuring.
!
• Also, proteases are crucial in the invasion process as they are able to cut their way through
other proteins and thereby into cells and tissues.
!
• Proteases are glycosylated, and the carbohydrate moiety on their surface is often crucial
for recognising and binding their target protein.
!
• Changes in glycosylation pattern (say owing to mutations) might affect protease functions
and thereby invasion.
Arpita Banerjee

25. 25
Hypothesis on glycosylation
Glycosylation is involved in all the three major steps of cancer progression.
Therefore, mutations affecting glycosylation sites on proteins
could be a determining factor in progression of the disease.
Arpita Banerjee

26. Selected References
The glycobiology of brain tumors: disease relevance and therapeutic potential Expert Rev.
Neurother (2009) 9(10), 1529–1545
!
Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in
gastric cancer. Oncogene (2016); 35(13): 1619-1631
!
Cysteine proteases of human hookworm Necator Americanus as virulence factors and
implications for drug design with anti-heparin and heparin analogs: A bioinformatics study.
(2017). BioRxiv preprint.
Arpita Banerjee

27. Thank you