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Studies Describe Stromal Cell Role in Aggressive Colorectal Cancer Signature

NEW YORK (GenomeWeb) – The gene expression patterns in tumor-adjacent stromal cells appear to be particularly telling when trying to predict outcomes for patients with some colorectal cancer subtypes, new research suggests.

Studies by independent research teams reporting in Nature Genetics today delved into the stromal-like expression signatures detected in a subset of CRC tumors known for enhanced treatment resistance and diminished disease-free survival times.

In the first of these studies, a team from Italy, Romania, and Belgium explored the interplay between tumor and stromal cells, focusing on a colorectal cancer subtype called "SSM," which displays transcriptional patterns that resemble stem, serrated, and mesenchymal cell-like features.

Such characteristics were suspected of stemming from diminished differentiation, a shift toward more stem cell-like features, and epithelial-to-mesenchymal transition in the tumor cells themselves. But the latest findings suggest that these traits may be more closely tied to expression by stromal cells than to tumor tissue expression.

Using existing expression data for hundreds of colorectal cancer tumors — together with mouse model experiments involving CRC patient-derived xenografts  — the researchers determined that characteristic transcriptional signatures associated with the SSM subtype actually reflect expression in stromal cells that flank or infiltrate the tumor.

That group's follow-up experiments also pointed to a rise in treatment resistance in samples marked by enhanced expression of transcriptional signatures from several stromal cell types — particularly cancer-associated fibroblasts, leukocytes, and endothelial cells.

"Collectively, these results reinterpret the [epithelial-to-mesenchymal transition] and stemness traits typically ascribed to epithelial cancer cells as prevalent stromal contributions," the study's authors wrote, "and provide new stromal scores that may prove helpful in advancing CRC prognosis and response prediction." 

For their part, researchers from the Institute for Research in Biomedicine in Barcelona and elsewhere used array-based expression profiles from roughly 1,000 CRC patients in three cohorts to determine that stromal cells were behind the transcriptional signatures previously linked to treatment resistance and poor patient survival — results they verified with the help of immunohistochemical staining and bioinformatics. 

"By focusing on the genetic program of the tissue surrounding the tumor we can identify the vast majority of patients that will experience relapse," senior author Eduard Batlle, head of IRB Barcelona's colorectal cancer lab, said in a statement. "This would allow better discrimination of which patients to treat and follow up, as the use of radiotherapy or chemotherapy would benefit only this group."

Members of the team are reportedly developing a test called Colostage to predict metastasis risk in individuals with colorectal cancer based on features found in stromal tissue.

In their current analysis, the researchers found evidence of stromal and tumor cell interactions that hinge on signaling by the TGF-beta pathway. Though enhanced activity of the TGF-beta pathway appears to dial down growth of epithelial CRCs, they explained, its expression in stromal cells is suspected of boosting the risk of tumor initiation and spread.

For instance, the investigators managed to curb the progression of CRC patient-derived tumor organoids using a compound called LY2157299 that interferes with TGF-beta signaling, prompting them to argue in favor of more extensive development and testing of treatments that target the pathway.