{"entity":{"id":"paper-isella-stromal-contribution-colorectal-transcriptome-nat-genet-2015","kind":"paper","name":"Stromal contribution to the colorectal cancer transcriptome","aka":[],"tldr":"The gene-activity subtype with the worst prognosis turned out not to be a property of the cancer cells at all. Growing human tumours in mice showed that its defining genes are switched on in the surrounding connective tissue.","summary":"Genes upregulated in the poor-prognosis stem, serrated and mesenchymal transcriptional subtype are also prominently expressed by stromal cells, raising the possibility that the transcripts derive from stroma rather than epithelial cancer cells. Colorectal cancer expression data from patient-derived xenografts, where mouse stroma supports human cancer cells, allowed species-specific expression analysis, which showed that the subtype's messenger RNA levels were mostly due to stromal expression. Transcriptional signatures built to report the abundance of cancer-associated fibroblasts, leukocytes or endothelial cells were all significantly higher in human samples of that subtype. High fibroblast signature expression was associated with poor prognosis in untreated disease, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer.","asOf":"2026-09-24","links":[{"label":"Isella et al., Nat Genet 2015: the stromal contribution to the colorectal cancer transcriptome","url":"https://doi.org/10.1038/ng.3224"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25706627/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["rna-seq"],"targets":[],"drugs":[],"companies":[],"institutions":["candiolo"],"pathways":["caf-activation-desmoplasia","tumor-microenvironment","emt"],"terms":["cms-subtypes","desmoplasia"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2015,"doi":"10.1038/ng.3224","pmid":"25706627","authors":"Isella C, Terrasi A, Bellomo SE, et al.","paperType":"translational","findings":["Mesenchymal subtype transcripts come mostly from stroma, shown by species-specific analysis in patient-derived xenografts.","Fibroblast signature expression associated with poor prognosis in untreated disease.","Joint stromal signature expression predicted radiotherapy resistance in rectal cancer."],"whatItMeans":"It means a CMS4 call on a bulk sample partly measures how much stroma was in the block, which is both a caution for the classification and a pointer to the stroma as the thing to treat.","caveats":["Xenografts lack a human immune system, so the leukocyte component is modelled indirectly.","Retrospective prognostic associations."],"changedPractice":false},"route":"/key-papers/paper-isella-stromal-contribution-colorectal-transcriptome-nat-genet-2015/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"}],"institution":[{"id":"candiolo","kind":"institution","name":"Istituto di Candiolo IRCCS (FPO)","route":"/institutions/candiolo/"}],"pathway":[{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"}],"term":[{"id":"cms-subtypes","kind":"term","name":"Consensus molecular subtypes (CMS1-4)","route":"/terms/cms-subtypes/"},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/"}],"journal":[{"id":"nature-genetics","kind":"journal","name":"Nature Genetics","route":"/journals/nature-genetics/"}]}}