Cell competition Flashcards
What is cell competition?
- eliminated damaged, slow growing and misspecified cells from tissues
- loser cells can be viable on their own but their interaction with winner cells triggers their death or differentiation
- slows ageing and disease
How does cell competition get triggered?
- many mutations can turn cells into winners or losers compared to wild type cells
- wnt
- myc
- hippo
- p53
What are minute mutations?
mutations in ribosome genes
What is minute competition in cell competition?
- heterozygous minute mutations in drosophila are viable but developmentally delayed
- when in range of WT cells they are induced to apoptose and WT cells grow larger and outcompete them
How can changes in myc activity make cells winner or losers?
- if cells lose a copy of myc they become losers to WT cells
- if you give cells a 3rd copy of myc they become supercompetitors and wipe out surrounding WT cells
In what organisms has this mechanism of myc-induced competition been seen? What does this show?
- drosophila, mouse embyro, mouse ESCs, post natal mouse heart
- shows that myc-induced competition is conserved acrss organs and species
What would be the expected mechanism of minute-induced cell competition?
that minute mutations would decrease translation contributing to loser status but this is not true as cells expressing translational repressors are not losers to WT cells
What is the reason for the loser status of minute-mutation cells?
- mutant ribosomes require high levels of degradation and the cell mechanisms cant keep up
- you can get build-up of ubiquitin-rich protein aggregates that cannot be degraded fast enough by the proteasomeHo
How does the accumulation of protein aggregates contribute to loser status?
- causes proteotoxic stress seen in ageing and degenerative diseases
- decreased proteostasis
- may be relevant in cancers carrying ribosome mutations
How do we know that protein aggregates contribute to loser status?
- TF FOXO improves proteostasis and proteasomal degradation
- overexpression of FOXO in minute cells stops their death by WT cells
- while triggering the overexpression of protein aggregates leads to loser status
How are minute-mutant cells relevant to cancer?
- there are 80 ribosome genes so a high chance of one being mutated
- single copy loss of ribosome genes occurs in 43% of cancers
- cancer cells may be concealed loser cells that have aquired additional mutations due to selective pressure
- unmasking loser status?
What does scribble KO do in terms of cell competition?
- makes cells losers to WT
- eliminated through apoptosis and delamination when co-cultured with WT cells
- viable on their own
Why does scribble KO cause cells to be losers?
- makes cells hypersensitive to compaction
- p53 pathways are enriched in these cells
which may be making them mechanical losers
How do we know that increased p53 can make cells mechanical losers?
- nutilin is a chemical activator of p53
- it can increase p53 dose dependently
- WT cells can survive with low levels of nutilin present
- when co-cultured with p53 negative cells they are outcompeted
How does increaseed p53 lead to mechanical loss?
- renders cells hypersensitive to crowding
- compaction increases p53 which increases cell death
- this many be the mechanism to destroy damaged cells to make way for new better ones
What might be the link between p53-induced mechanical competition and cancer?
- p53 is frequently mutated in cancer and may be helping cancer cells avoid mechanical competition
- cells with decreased p53 outcompete WT cells so wont be killed
- may even kill surrounding cells and free up space for their own growth
What is the proposed role for cell competition in tumour promotion?
many mutations seen in cancer allow cells to become supercompetitors allowing them to kill non-tumour cells around them and free up space to grow
What was the first demonstration that cell competition plays a role in tumourgenesis?
- APC loss leads to hyperplasia in drosophila
- WT cells are 4x more likely to die when next to APC mut tumour cells
- APC -/- cells are therefore killing their unmutated neighbours
- killed both stem and differentiated cells
How do APC-/- cells inact cell competition?
- inhibit wnt signalling in their neighbours
- produce wnt inhibitor notum
- APC-/- cells don’t degrade b-catenin leading to build up without receptor binding
- these cells are therefore unaffected by notum so only WT cells are affected
What happens when APC-/- cells can’t kill their neighbours?
- can be induced by apoptosis inhibitors
- APC growth doesn’t occur
- cant free the space around them so receive less signals to grow and have nowhere to grow to
- could apoptosis inhibitors actually reduce tumourgenesis?
What is EDAC?
epithelial defence against cancer
- the tumour-suppressive properties of healthy epithelia to kill their oncogenic neighbours
What are the pros + cons of using apoptosis inhibitors in cancer?
- can inhibit the super-competitor status of tumour cells and protect normal cells
- not feasible as therapy as apoptosis inhibition can also benefit tumour cells
What are the aims of cell competition therapy?
- to inhibit the super competitor status of tumours
- allow EDAC by reducing toxicity of chemotherapy or radiotherapy
- unmasking the lose status of cancer cells
How can cancer treatment reduce EDAC?
- WT cells are also killed or damaged in exposure to drugs and therapies
- provides more space for tumours to grow and compromises the natural EDAC response
What is peritumoural activation?
activation of or by the cells surrounding a tumour
What is the hippo pathway?
- tumour suppressor pathway
- regulates the TF YAP
- YAP promotes proliferation and stemmness
What happens in Akt+/+ tumours if YAP is overexpressed in peritumoural cells?
- tumours cannot grow and are even wiped out
- when YAP is removed tumours come back
- can grow without YAP as log as their neighbouring cells do not express it
How are these findings about YAP relevant to cancer treatment?
- oncogenic signalling in non tumour cells may be an unexplored strategy
- further research needed
