Colon cancer

right side

MSI pathway of development - serrated pathway
MMR mutations
BRAF V600
CIMP phenotype

left side

CIN tumours
classical pathway = normal - adenoma - adenocarcinoma

MSI pathway

MMR mutations
BRAF mutation
TGFBR, IGFR, BAX mutations

CIN pathway

APC inactivation - KRAS mutation - SMAD2/4 loss - TP53 loss

evidence that mutations occur at specific points

molecular clock analysis
sequence tumours and see when passenger mutations become embedded
calibrate timeline of incurred cancer mutations

survival of CRC cells in circulation

bind platelets to protect from immune cells
upregulate survivin to counteract anoikis

cachexia

metabolic wasting syndrome of muscles without fat loss
increase pro inflammatory cytokines due to tumour - can cross BBB - interact with luminal surface of brain endothelial cells - release of substances that affect appetite

role of TNFa in cachexia

increases gluconeogenesis, lipolysis and proteolysis
decreased synthesis
UCP expression

IL1 role in cachexia

causes increase in plasma tryptophan concentration
increases serotonin levels
increases early satiety and suppresses hunger

treatment of cachexia

derivatives of progesterone improves appetite and weight
ghrelin improves lean and total body mass
MC4 antagonists

molecular drivers of colon cancer

wnt or EGFR pathway components

wnt pathway

off = APC complex Ub tags beta catenin for degradation
on = wnt binds FZD - recruits AXIN1/GSK3/APC complex - beta catenin free to dimerise with TCF in nucleus - transcribes target genes

APC

beta catenin binding and regulation domains
mutations in cancer maintain downregulation domains to restrict beta catenin to avoid cell death but also drive cancer progression
moonlights to coordinate kinetochore attachment - mutant leads to CIN

CRC organoids

can see relationship between mutations and phenotypes
can develop from CRC patients and test drugs

conditional mouse model - triple apc, kras and TP53 mutation

tamoxifen induced
removes stop before ras mutant
removes p53
removes stop before rtTA which binds TRE to induce apc shRNA
in Lgr5 stem cells

CMS1 - MSI-H

right sided
hypermutated
frequent BRAF mutations
immune activated
responds well to ICIs
lower survival after relapse

CMS2

usually left sided
MSS
CIN
wnt and myc activation
best overall survival and relapse free survival

CMS3

mixed MSS/MSI
KRAS mutations
metabolic deregulation
intermediate survival

CMS4

mesenchymal
CIN
MSS
EMT upregulation
TGFB
worst overall survival and relapse free survival
tendency to metastasise