COLITIS-ASSOCIATED COLON CANCER: EXPLORING THE DCLK1-S-MMP13-P53 AXIS

Abstract

Chronic intestinal inflammation in patients with inflammatory bowel diseases (IBD) significantly increases the risk of colorectal cancer (CRC). Tuft cells in the intestine marked by doublecortin-like kinase-1 (DCLK1), are long-lived chemosensory cells with newly identified roles in colitis as epithelial ablation of DCLK1 worsens disease outcome. DCLK1 exists in long and short isoforms (DCLK1-L and DCLK1-S). Hypermethylation of DCLK1 alpha promoter encoding DCLK1-L particularly in CRC, allows switching to the DCLK1-S isoform that confers a more invasive tumor phenotype. In an infectious colitis model, we recently discovered that DCLK1-S is predominantly expressed in Ly6G+;MHCII- neutrophils that coincides with elevated levels of CXCL1/KC and MMP13 expression in the colon. In an unbiased molecular docking study, DCLK1’s kinase domain was found to interact with the catalytic domain of MMP13. MMP13 plays a crucial role in the modulation of extracellular matrix (ECM) degradation and cell-matrix interactions and wild type and mutant p53 differentially regulate MMP13 gene expression. Mutations in TP53 (tumor suppressor p53) are crucial for neoplasia initiation in IBD patients and are observed in 50-85% of colitis-associated colon cancers (CACCs). We further observed that p53 mutation status dictates DCLK1-S expression in colon cancer cells and in mice mutant for p53, expression of DCLK1-S and MMP13 correlated with neutrophilic inflammation and crypt hyperplasia. We will expand on these novel discoveries by employing high fidelity proteomic and phosphoproteomic studies and decipher how DCLK1-S-MMP13-p53 axes stimulate fibrosis, tumorigenesis, and tumor progression. These studies are expected to lead to therapeutic avenues to target CACCs.