Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5) expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human mucin 1–transgenic (MUC1-transgenic) mouse models of CACC, targeting the MUC1-C oncogenic protein suppresses the (a) Lgr5 ⁺ ISC population, (b) induction of Myc and core pluripotency stem cell factors, and (c) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter, and activates LGR5 expression. We also show in CRC cells that MUC1-C induces cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2, and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal, and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis, and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a potentially previously unrecognized target that is druggable for treating progression of colitis and CRC.

The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 and IRF1 are essential effectors of type I and II IFN pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in triple-negative breast cancer (TNBC) cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLS) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA TNBC cells enhanced carboplatin-induced DNA damage and the loss of self-renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal, and tumorigenicity in olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC tumors corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes (TIL). These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion. Implications: MUC1-C is necessary for PBRM1-driven chromatin remodeling in chronic activation of IFN pathway genes that promote DNA damage resistance and immunosuppression.

The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) cells in association with chromatin remodeling. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN-γ) pathway. We show that MUC1-C→ARID1A/BAF signaling induces IFNGR1 transcription and that MUC1-C-induced activation of the NuRD complex suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. We further demonstrate that MUC1-C and PBRM1/PBAF are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune tumor microenvironment (TME), and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Analyses of scRNA-seq data further demonstrate that MUC1 correlates with cancer stem cell (CSC) and IFN gene signatures across CRPC cells. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-γ pathway and induction of chromatin remodeling complexes in linking the CSC state with immune evasion.

The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged‐1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens. Expression of JAG1 and E‐cadherin and their associations with clinicopathologic characteristics, overall survival (OS) and relapse‐free survival (RFS) were evaluated. In vitro studies using compounds to regulate intracellular signaling and small interfering RNA to silence JAG1 were performed in a colon cancer cell line. JAG1 expression in cancerous tissues was weak, moderate or strong in 32%, 36% and 32% of specimens, respectively, and correlated with histologic type and T stage. In multivariate analysis, JAG1 expression, histologic type and lymphatic invasion independently correlated with OS and RFS. The combination of high JAG1 expression and low E‐cadherin expression had an additive effect toward poorer OS and RFS compared with the low JAG1/high E‐cadherin expression subtype. A significant correlation between JAG1 expression and KRAS status was detected in groups stratified as high E‐cadherin expression. In vitro studies suggested that RAS‐MEK‐MAP kinase and the Wnt pathways positively regulated JAG1 expression. Gene silencing with siJAG1 indicated that JAG1 promotes the transition from epithelial to mesenchymal characteristics and cell growth. High expression of JAG1 is regulated by various pathways and is associated with poor prognosis through promoting the epithelial to mesenchymal transition and cell proliferation or maintaining cell survival in CRC.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. TNBC progression is associated with expansion of cancer stem cells (CSCs). Few insights are available regarding druggable targets that drive the TNBC CSC state. This review summarizes the literature on TNBC CSCs and the compelling evidence that they are addicted to the MUC1-C transmembrane protein. In normal epithelia, MUC1-C is activated by loss of homeostasis and induces reversible wound-healing responses of inflammation and repair. However, in settings of chronic inflammation, MUC1-C promotes carcinogenesis. MUC1-C induces EMT, epigenetic reprogramming and chromatin remodeling in TNBC CSCs, which are dependent on MUC1-C for self-renewal and tumorigenicity. MUC1-C-induced lineage plasticity in TNBC CSCs confers DNA damage resistance and immune evasion by chronic activation of inflammatory pathways and global changes in chromatin architecture. Of therapeutic significance, an antibody generated against the MUC1-C extracellular domain has been advanced in a clinical trial of anti-MUC1-C CAR T cells and in IND-enabling studies for development as an antibody–drug conjugate (ADC). Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.