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Circular RNAs (circRNAs) have recently gained substantial attention in the cancer research field where most, including the putative oncogene ciRS-7 (CDR1as), have been proposed to function as competitive endogenous RNAs (ceRNAs) by sponging specific microRNAs. Here, we report the first spatially resolved cellular expression patterns of ciRS-7 in colon cancer and show that ciRS-7 is completely absent in the cancer cells, but highly expressed in stromal cells within the tumor microenvironment. Additionally, our data suggest that this generally apply to classical oncogene-driven adenocarcinomas, but not to other cancers, including malignant melanoma. Moreover, we find that correlations between circRNA and mRNA expression, which are commonly interpreted as evidence of a ceRNA function, can be explained by different cancer-to-stromal cell ratios among the studied tumor specimens. Together, these results have wide implications for future circRNA studies and highlight the importance of spatially resolving expression patterns of circRNAs proposed to function as ceRNAs. The circular RNA named ciRS-7 is overexpressed in human cancers, however, its spatial cellular expression patterns have not been explored. Here, the authors show that ciRS-7 is not expressed in colon cancer cells, but abundant in stromal cells within tumours, and that cancer-to-stromal cell ratios contribute to correlations between ciRS-7 and miR-7 target genes.

Predicting recurrences in patients with stage II colon cancer remains a clinical challenge. This study aimed to uncover connections between gene expression, clinicopathological characteristics, and recurrence in patients with stage II colon cancer. Gene expression profiling was conducted on primary tumors from 94 well-characterized patients with stage II colon cancer using the PanCancer IO 360™ panel from NanoString Technologies, which includes 770 mRNAs related to tumor progression and the tumor microenvironment. Unsupervised hierarchical clustering, differential gene expression (DEG) and survival analyses were used to describe the relationship between gene expression, clinicopathological characteristics, and recurrence. Unsupervised hierarchical clustering revealed distinct gene expression patterns in pT4 tumors, particularly in pathways involving immune cell localization and myeloid cell activity. DEG analysis identified 156 differentially expressed genes in pT4 versus pT3 tumors, including the important chemokines, CCL2 and CXCL8 , and the cytokine LIF . In addition, 35 upregulated genes associated with migration and extracellular processes were identified in patients with recurrence. Finally, SLC2A1 and VEGFA emerged as independent prognostic markers for time to recurrence and overall survival. In conclusion, this study unveiled distinct gene expression patterns in advanced pT4 tumors, and identified independent prognostic biomarkers that may prove useful in stage II colon cancer.

The formation of budding cancer cells at the invasive front of solid tumors is one of the first steps of metastasis. However, this process is still incompletely elucidated. Here, we used spatial molecular imaging to disentangle the complex interactions between cancer cells and the tumor microenvironment at the invasive front of colorectal tumors. Employing a 1000-plex gene panel, we defined all major cell types in tumors and adjacent normal tissue with accurate spatial information. Individual cancer cell clusters were located together, consistent with an expected mutation- and epigenetic-driven clonal evolution. However, cancer cell clusters encompassing budding cells exhibited a markedly different spatial distribution as they also contained cells that were scattered around the periphery of the main cancer cell masses. Moreover, these cells were frequently in contact with cancer-associated fibroblasts (CAFs) and underwent broad gene expression changes, mainly related to epithelial-mesenchymal transition (EMT), remodeling of the extracellular matrix (ECM), and migration. In addition, we defined an 11-gene signature ( TYK2 , IL2RG , KRT17 , HLA-B , NPPC , WIF1 , IL32 , B2M , CCND1 , CRIP1 , ITGB1 ), which characterizes cancer cells en route to metastasis and is associated with inferior outcomes. Collectively, our findings suggest that CAFs induce pro-invasive gene expression changes involved in EMT, ECM remodeling, and migration. Single-cell spatial transcriptomics reveals that CAFs at the invasive front of colorectal tumors induce pro-invasive changes in budding cancer cells, characterized by an 11-gene signature linked to metastasis and poor prognosis.

Tumor budding, a biomarker traditionally evaluated using hematoxylin and eosin (H&E) staining, has gained recognition as a prognostic biomarker for stage II colon cancer. Nevertheless, while H&E staining offers valuable insights, its limitations prompt the utilization of pan-cytokeratin immunohistochemistry (IHC). Consequently, this study seeks to evaluate the prognostic significance of tumor budding using IHC in a contemporary cohort of stage II colon cancer patients, aiming to deepen our understanding of this critical facet in cancer prognosis. We conducted a retrospective, population-based cohort study including 493 patients with stage II colon cancer and evaluated tumor budding using IHC, following the H&E-based guidelines proposed by the International Tumor Budding Consensus Conference Group. Correlation between H&E-based and IHC-based tumor budding was assessed using a four-tiered scoring system that included a zero budding (Bd0) category. Survival analyses explored the prognostic significance of tumor budding assessed by IHC and H&E. As expected, IHC-based tumor budding evaluation yielded significantly higher bud counts compared to H&E (p < 0.01). Interestingly, 21 patients were identified with no tumor budding using IHC. This was associated with significantly improved recurrence-free survival (HR = 5.19, p = 0.02) and overall survival (HR = 4.47, p = 0.04) in a multivariate analysis when compared to tumors with budding. The Bd0 category demonstrated a 100% predictive value for the absence of recurrence. In conclusion, IHC-based tumor budding evaluation in stage II colon cancer provides additional prognostic information. The absence of tumor budding is associated with a favorable prognosis and may serve as a potential marker for identifying patients with no risk of recurrence.