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cancer > 14. cancer, iPSC reprogramming and de-differentiation > Flashcards

14. cancer, iPSC reprogramming and de-differentiation Flashcards

1
Q

where do tumour initiating cells come from?

A

uncontrolled proliferation of stem cells/progenitor cells/differentiated cells

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2
Q

over proliferation does not necessarily mean cancer in stem cells but what may it mean?

A

build up of mutations more rapidly

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3
Q

why are tumour initiating cells less likely to come from differentiated cells?

A

they are post mitotic and a lot more reprogramming is required in these cells

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4
Q

what can be learnt from reprogramming in relation to formation and proliferation of cancer stem cells?

A

they give us insight into how cancer can be initiated

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5
Q

what are pluripotent stem cells?

A

stem cells that are able to give rise to ll three germ layers

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6
Q

what are multipotent stem cells?

A

stem cells that are tissue specific

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7
Q

what is Waddington’s epigenetic landscape? and what does this landscape imply?

A

a metaphor for how gene regulation modulates development
>as changes in gene expression and epigenetics occur, the cells has limited options on what it can become (becomes more lineage restricted)
- that cells cannot go back up the landscape

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8
Q

what was their evidence for soon after Waddington’s epigenetic landscape was established?

A

it possible for cells to de-differentiate and climb back up the mountain

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9
Q

what did John Gurdon do in the 60s?

A

nuclear transfer

>cloned the first animal by transplanting somatic cells nuclei into a Xenopus oocyte

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10
Q

what was shown about oocyte cytoplasm?

A

components of the egg cytoplasm are sufficient to reprogram the transplanted nuclei into a pluripotent state

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11
Q

what did John Gurdons experiments also show?

A

that every cell in the body contains the entire genome

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12
Q

when was the first mammal cloned?

A

1996 - Dolly

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13
Q

when were iPSC first developed?

A

2006

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14
Q

what are the four Yamanaka factors

A
  • Oct4
  • Klf4
  • Sox2
  • c-Myc
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15
Q

what can iPSC be used for?

A

modelling disease and testing therapeutics

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16
Q

what was in vivo reprogramming shown to do? and how was this done?

A

cause teratomas and iPSC with totipotent features

>transgenic mice that can express the OKSM factors in all cells.

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17
Q

what are teratomas?

A

these are cancers which form from cells that resemble all three germ layers.

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18
Q

tumours can form in many different tissues in this mice when OSKM factors are expressed in mice. what is interesting about this?

A

even when there are no immature cells in a tissue tumours can still arise here i.e. reprogramming took place of fully differentiated cells in vivo

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19
Q

what are the key barriers for reprogramming and tumour initiation?

A

DNA methylation
histone modification
compacted chromatin - lineage restricted TFs they recruit complexes like polycomb and HP1

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20
Q

how is DNA methylation a barrier to reprogramming?

A

it most stable epigenetic mark

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21
Q

what was though about DNA methylation until recently?

A

it was lost through cell division

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22
Q

what discovery suggested that DNA methylation could be activity lost?

A

presence of 5-hydroxymethyl cytosine (5hmC)

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23
Q

what two family of proteins have defined to convert methyl cytosine back to cytosine?

A

TET -convert 5mC to 5hmC (5-hydroxylmethyl cytosine)

TDG - reconstitutes cytosines (makes abasic site and allow for base excision repair to place)

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24
Q

how are TET proteins activated in the reprogramming process?

A

by OSKM factors

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25
Q

when TET and TDG are KO, what does this mean?

A

reprogramming is not possible

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26
Q

what can replace Otc4 in reprogramming?

A

TET1 - ability to remove 5mC marks is essential for reprogramming

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27
Q

are tet proteins up-regulated in cancer? what might affect this?

A

you would expect it to be upregulated to removed methylation, but it is not
>people look at cancer once it has established - TET may be present in initiation stage but this is v hard to study

28
Q

what is mutated in several types of leukaemia? and some cases of acute leukaemia?

A

TET

DNMT3A (the enzyme which adds methylation)

29
Q

what is dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers?

A

5hmC levels

30
Q

why might tumour cells want low expression of TET?

A

> cancer cells, once formed, can try to prevent any changes in DNA methylation (inhibit differentiation and maintain division)
so that they can keep their tumour supresses supressed, TET might removed suppression

31
Q

what can inhibit the function of TET and lysine demethylases?

A

metabolic changes

32
Q

what are neomorphic mutations? and where might they occur? and what is this in terms of cancer?

A

mutation that gives protein/enzyme new function
>IDH lead instead to the accumulation of 2-GH
>oncometabolite inhibits TET and lysine demethylases
- this is another way that cancer cells can limit plasticity and DNA methylation changes in cells

33
Q

what does this mutation in IDH lead to?

A
  • hypermethylation throughout genome

- increase of stem and progenitor cells relative to differentiated cells

34
Q

IDH is mutations in 80% of gliomas but TET is rarely mutated why might this be?

A

the brain might rely more on histone modification to limit plasticity rather than DNA methylation

35
Q

what ability is often lost once a tumour is initiated?

A

the ability to removed DNA methylation (e.g. TET activity) - reduces capacity to differentiate and keeps cells dividing in constant state

36
Q

why might TET activity may inhibit tumour growth? but what does repression of TET and IDH gene allow?

A

it may allow the cells to differentiate
>it will have the ability to change in its microenvironment
>give tumour advantage to adapt to perturbations in the environment e.g. chemotherapy/moving to different parts of body

37
Q

what can happen if cells have limited plasticity (in terms of treatment)?

A

you can use cancer stem cell targeted therapies and kill all the cancer stem cells then the tumour will not have the ability to continue to grow

38
Q

why does relapse occur in traditional therapies?

A

some cells (including cancer stem cells) may be left behind

39
Q

what can happen is cells have plasticity (in terms of treatment)?

A

if cells in the tumour can regain some plasticity then even when the tumour is targeted with cancer stem cell targeted therapy, the cancer stem cells will die, but some cells can then de-differentiate into new cancer stem cells
>patient will relapse due to residual plasticity

40
Q

what can help tumours evade immunotherapy treatment?

A

de-differentiation

41
Q

what is adoptive cell transfer?

A

immunotherapy in which T cells with receptors that recognise cancer specific antigens are injected into the patient

42
Q

how can cancer cells avoid adoptive cell transfer?

A

> T cells recognise and destroy cancer cells
some cancer cells dedifferentiated, they lose tumour specific antigen and therefore avoiding the T cells
tumour able to regrow after therapy

43
Q

how efficient is Yamanaka’s initial reprogramming method ?

A

quite inefficient

44
Q

how can Yamanaka’s initial reprogramming method be optimised?

A

KO MBD3 – this binds methylated residues in DNA, part of the NurD repressive complex
>KO leads to less compact chromatin

45
Q

what does Oct4 interact with?

A

thrithorax complex component WDR5

>WDR5 recruits thrithorax complex to pluripotency gene promoters and cell cycle genes and promotes gene activation

46
Q

what else does Oct4 interact with?

A

a lysine demethylase - removes repressive marks on pluripotency genes

47
Q

over expression of what can enhance reprogramming?

A

BRM - ATP-dependent remodelling complex
remodels nucleosomes and opens up chromatin
- over expression of BRM also associated with tumour development in prostate cancer

48
Q

what is not essential for reprogramming, it accelerates the process?

A

Myc -potent pro-proliferation oncogene that is highly amplified in many cancers

49
Q

what does myc do in cancers cells?

A

> ramps up metabolism and allow cells to grow faster

>this generates metabolic intermediates that are essential for reprogramming

50
Q

does myc function as a hetero or homo dimer?

A

heterodimer - when myc dimerises with Max this activates gene expression

51
Q

what happens when Max dimerises with Max and Mad?

A

this represses gene expression

52
Q

some cells cannot proliferate if there is no Myc function, what is this called?

A

oncogene addiction

53
Q

they made transgenic mouse that can conditionally express the dominant negative form of Myc induced by doxycycline – temporarily inhibited Myc function in mice, what was shown in these mice?

A

these Myc form homodimers in cells - no Myc left to bind Max to turn on genes to allow cells to divide

54
Q

what can transient expression of dominant negative c-Myc do?

A

can stop K-ras induce lung tumours, and lead to their regression

55
Q

what is a side effect of expression dominant negative c-Myc?

A

this stops all stem cells from dividing - mice can tolerate this and recover

56
Q

what therapeutic idea lead from this transgenic mice study?

A

drug that inhibits Myc from binding Max could mimic this and potentially be revolutionary

57
Q

is maintaining differentiated state an active process?

A

recent work has revealed that maintaining a differentiated state can be an active process

58
Q

give an example of how maintaining differentiation is an active process, and what are these factors often associated with?

A

mutations of certain key factors can cause cells to de-differentiate into less differentiated state or even stem like state
>tumour formation

59
Q

give an example of two lineage specific guardians and how perturbing them can result in de-differentiation

A

> lola ablation causes de-differentiation in immune neurones into NSCs
prox1 ablation causes trans-differentiation of lymphatic cells to blood cells

60
Q

is differentiation more like climbing up a mountain than rolling down a valley?

A

as cells differentiate do we need to have barriers to stop them rolling back down?
it may be a bit of both - these factors involved in active maintenance are implicated in how caners initiate

61
Q

plasticity in gut epithelial cells can lead to tumour initiation, how does this occur?

A

increased NF-κB and Wnt signalling in post-mitotic intestinal cells causes dedifferentiation
>this leads to hyperplasia

62
Q

why do people that have inflamed guts get cancer more easily?

A

they have high levels of NF-κB

63
Q

recent work has highlighted strong parallels between what two processes?

A

iPS reprogramming and tumour initiation

64
Q

what is the ability to alter DNA methylation states closely linked to?

A

cell plasticity

65
Q

how is cell plasticity a blessing and a curse to cancer cells?

A

want plasticity to initiate and then once cancer has formed you want to prevent plasticity - prevent differentiation and keep proliferating

66
Q

what do different cell types have in terms of intrinsic plasticity and guard against de-differentiation?

A

different states of intrinsic plasticity and different methods to guard against de-differentiation

cancer (24 decks)

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