Targeting tumor-associated MUC1 overcomes anoikis-resistance in pancreatic cancer

The third leading cause of cancer-related deaths in the United States is pancreatic cancer, more than 95% of which is pancreatic ductal adenocarcinoma (PDA). The incidence rate of PDA nearly matches its mortality rate and the best treatment till date is surgical resection for which only 25% are eligible. Tumor recurrence and metastasis are the main causes of cancer-related mortality. MUC1 is a transmembrane glycoprotein expressed on most epithelial cells. It is overexpressed and aberrantly glycosylated in cancer and is known as tumor-associated MUC1 (tMUC1). More than 80% of PDAs express tMUC1. A monoclonal antibody called TAB004 has been developed specifically against human tMUC1 extracellular domain. We report that treatment with TAB004 significantly reduced the col-ony forming potential of multiple PDA cell lines while sparing normal pancreatic epithelial cell line. Binding of TAB004 to tMUC1 compromised desmosomal integrity, induced ER stress and anoikis in PDA cells. The mecha-nisms underlying TAB004's antitumor effects were found to be reduced activation of the EGFR-PI3K signaling pathway, and degradation of tMUC1, thereby reducing expression of its transcriptional targets, c-Src and c-Myc. This reduction in oncogenic signaling triggered anoikis as indicated by reduced expression of antiapoptotic pro-teins, PTRH2 and BCL2. TAB004 treatment slowed the growth of PDA xenograft compared to IgG control and enhanced survival of mice when combined with 5-FU. Since TAB004 significantly reduced colony forming poten-tial and triggered anoikis in the PDA cells, we suggest that it could be used as a potential prophylactic agent to curb tumor relapse after surgery, prevent metastasis and help increase the efficacy of chemotherapeutic agents.

Automated summary

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDA), is a major cause of cancer-related deaths in the United States. Surgical resection is the best treatment option, but only a small percentage of patients are eligible. Recurrence and metastasis are the main reasons for mortality. A monoclonal antibody named TAB004 has been developed to target tumor-associated MUC1 (tMUC1), which is expressed in over 80% of PDAs. Treatment with TAB004 has shown significant effects in reducing colony-forming potential in PDA cells and inducing cell death. The mechanism involves disruption of cellular integrity, activation of ER stress and anoikis, and inhibition of oncogenic signaling pathways. TAB004 also exhibited promising results in mouse models, indicating its potential as a prophylactic agent to prevent tumor relapse, metastasis, and increase the efficacy of chemotherapy.