Single-cell sequencing analysis reveals CHURC1 as a non-canonical oncoprotein governing goblet cell-driven colorectal tumorigenesis.

Colorectal cancer (CRC) is a type of malignant tumor with an incompletely understood etiology, particularly concerning the specific cellular origins that trigger tumorigenesis. The precise cells that initiate the cancer transformation within the complex tissue environment of the colon and rectum remain largely elusive, contributing to the challenges in the prevention and early detection of this disease. In this study, we employed single-cell RNA sequencing to analyze 14 samples from CRC tumors, intestinal polyps, and adjacent normal tissues collected from four patients with CRC. Our analysis revealed goblet cells as a potential novel cellular origin for CRC. By comparing significantly differentially expressed genes in goblet cell subpopulations between CRC and para-tumor tissues, and overlapping with a database of human transcription factors, we identified Churchill Domain Containing 1 (CHURC1) as being highly expressed in patients with CRC. We hypothesized CHURC1 as a transcriptional activator (TA) due to its incorporation of the Churchill domain. However, further comprehensive assays demonstrated that CHURC1 is not a TA and functions as a novel oncogene that promotes CRC proliferation and metastasis. Additionally, we discovered that CHURC1 significantly influences immune cytokine release within the tumor immune microenvironment and acts as a negative predictor for tumor-reactive T cells in immunotherapy. Collectively, our findings suggest that CHURC1, which is significantly differentially expressed in goblet cells, is a new oncogene implicated in CRC development, presenting a promising therapeutic target for its treatment.