Background 

Plasmacytoid urothelial carcinoma (PUC) is a rare but very aggressive type of bladder cancer. Unlike the more common forms of bladder cancer, PUC does not respond well to current treatments, and patients with PUC often have worse outcomes. A newer class of medications, called immune checkpoint blockade (ICB), helps the immune system find and attack cancer cells. These treatments have shown promise in some cancers, but for PUC, the evidence is mixed, and it is not clear if ICB works better than standard treatments. 

One key difference between PUC and regular bladder cancer is that PUC cells lose a protein called E-cadherin, which is normally present in bladder cancer cells. Early findings suggest that losing E-cadherin may change the types of immune cells inside tumors, which could affect how well ICB treatments work. However, we do not yet know if E-cadherin loss directly changes response to ICB, or exactly how it alters cancer cell behavior. 

What This Research Proposes to Address 

The researchers will use a cutting-edge tool called spatial transcriptomics to study human PUC tumors. Unlike traditional methods that mix all the cell information together, this method allows scientists to see each cell type and molecule in its exact location, like viewing pieces of fruit on a platter instead of blended in a smoothie. The team will also create PUC-like tumors in mice by removing E-cadherin from bladder cancer cells. They will then test whether ICB treatment is effective in these models. 

Why This Study Is Important 

This project aims to answer a critical question: “how are the immune cells different in PUC?” by understanding how the loss of E-cadherin changes tumors and their immune environment, researchers may discover why PUC resists treatment and how to overcome that resistance. The ultimate goal is to design better medications and improve survival for people diagnosed with this rare and difficult form of bladder cancer. 

Final Report Summary

Plasmacytoid urothelial carcinoma (PUC) is a rare but very aggressive type of bladder cancer. Many patients with PUC also have the more common type, called conventional urothelial carcinoma (CUC). Unfortunately, people with PUC usually do not respond well to the standard chemotherapy that is given before surgery. This makes it very important to find new medicines that work better for this cancer. 

One key feature of PUC is the loss of a protein called E-cadherin. In other cancers, losing this protein changes the way tumor cells interact with nearby cells, including immune cells. This study set out to learn more about how PUC is different from CUC and whether PUC might respond better to immunotherapy. 

To do this, researchers used a cutting-edge tool called spatial transcriptomics. This technology shows how different cell types are arranged in a tumor and which genes are active in those cells. The study found that in PUC, E-cadherin was missing, and other genes linked to aggressive cancer behavior were turned on. Researchers also saw clear differences in the types of immune cells in PUC compared to CUC. These findings could lead to new treatments designed specifically for patients with PUC. 

None Reported as of August 2025

UNC Physician Scientist Training Program, 2025, $160,000

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