Abstract
Stromal cells drive the transcriptional signature of poor-prognosis colorectal cancer subtypes.
Major finding: Stromal cells drive the transcriptional signature of poor-prognosis colorectal cancer subtypes.
Concept: TGFβ signaling in stromal cells promotes colorectal cancer cell tumor initiation and metastasis.
Impact: Stromal gene expression signatures may predict outcome and stratify patients for therapy.
Colorectal cancer is a heterogeneous disease that can be classified into subtypes based on distinct molecular and clinical features. Recent studies have used gene expression profiles to identify a colorectal cancer subtype characterized by expression of stem cell and mesenchymal genes that is associated with poor prognosis. Although it has been suggested that this subtype is comprised of cancer cells that have undergone a switch from an epithelial to a mesenchymal stem cell–like state, it is possible that stromal cells in the tumor microenvironment also contribute to the observed transcriptional profile. Isella and colleagues found that molecular classification of a large cohort of colorectal cancer samples highlighted a poor-prognosis stem/serrated/mesenchymal (SSM) subtype that displayed increased stromal content compared with other colorectal cancer subgroups. SSM signature genes were highly expressed in stromal cell populations within colorectal tumors, including cancer-associated fibroblasts (CAF), leukocytes, and endothelial cells, and species-specific expression profiling of patient-derived xenografts revealed expression of SSM genes in mouse stromal cells. Importantly, high expression of a stromal CAF signature correlated with poor prognosis in untreated patients, whereas upregulation of all three stromal signatures correlated with radiotherapy resistance in rectal cancer. Consistent with these findings, Calon and colleagues showed that genes associated with poor prognosis in colorectal cancer were highly expressed in tumor-associated stromal cells, in particular CAFs, and that high expression of the CAF gene cluster, including TGFβ-regulated genes, defined poor-prognosis tumor subtypes. Elevated TGFβ signaling in CAFs enhanced xenograft formation and tumor-initiating cell frequency. Moreover, inhibition of stromal TGFβ signaling reduced the metastatic potential of patient-derived colorectal cancer organoids, reinforcing the notion that oncogenic crosstalk between cancer cells and the tumor microenvironment contributes to both tumor initiation and progression. Together, these findings indicate that tumor-associated stromal cells contribute to the transcriptome of poor-prognosis colorectal cancer subtypes and drive tumorigenesis via TGFβ-mediated paracrine signaling.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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