Exploring the Tumor-Suppressing Potential of PSCA in Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is a tough cancer. Instead of stopping certain genes, we used their power to change tumors. Surprisingly, some proteins that usually help the cancer grow slowed it down when they were outside the cells. We found that one protein, called PSCA, which is usually bad for patients, could help if we placed it extracellularly. We conducted experiments to see how the cancer cells reacted, and we also looked at how a conditioned medium from the blood could affect the cancer. We found that PSCA could make the cancer cells weaker and less able to spread; it works together with other medicines that are used to fight cancer. This discovery could lead to new ways to treat cancer by using the same protein that was causing the issue. Overall, our study shows that some things that have a negative impact could be used to help fight this tough cancer. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly. We performed in vitro assays to assess the proliferation and migration and evaluated the tumor-modifying capacity of extracellular factors from peripheral blood mononuclear cells (PBMCs) in PDAC tissues. Molecular docking analysis, immunoprecipitation, Western blotting, and RNA interference were employed to study the regulatory mechanism. Extracellular PSCA recombinant protein notably curtailed the viability, motility, and transwell invasion of PDAC cells. Its anti-PDAC effects were partially mediated by Mesothelin (MSLN), another highly expressed tumor-associated antigen in PDAC. The anti-tumor effects of extracellular PSCA complemented those of chemotherapeutic agents like Irinotecan, 5-Fluorouracil, and Oxaliplatin. PSCA expression increased in a conditioned medium derived from PBMCs and T lymphocytes. This study unveils the paradoxical anti-PDAC potential of PSCA, hinting at the dual roles of oncoproteins like PSCA in PDAC suppression.