KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix.
Jin K KimMichael R MarcoSeo-Hyun ChoiXuan QuChin-Tung ChenMoshe ElkabetsLauren FairchildOliver ChowFrancisco M BarrigaLukas E DowKevin O'RourkeBryan SzeglinDmitry YarilinSho FujisawaKatia Manova-TodorovaPhilip B PatyJinru ShiaChristina LeslieJ Joshua SmithScott LoweRaphael PelossofFrancisco Sanchez-VegaJulio Garcia-AguilarPublished in: Molecular oncology (2021)
Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.
Keyphrases
- wild type
- extracellular matrix
- rectal cancer
- locally advanced
- gene expression
- end stage renal disease
- clinical trial
- ejection fraction
- chronic kidney disease
- newly diagnosed
- squamous cell carcinoma
- prognostic factors
- randomized controlled trial
- poor prognosis
- phase ii study
- metabolic syndrome
- cell death
- induced apoptosis
- type diabetes
- transcription factor
- study protocol
- cell proliferation
- genome wide
- long non coding rna
- signaling pathway
- patient reported outcomes
- weight loss
- high resolution
- adipose tissue
- drug induced
- young adults
- mass spectrometry