Background 

Researchers discovered that a certain enzyme, called AGL, plays an unexpected role in bladder cancer. Normally, AGL helps the body break down a type of stored sugar called glycogen. When AGL levels are low, bladder cancer tumors tend to grow faster and patients have worse outcomes.

The team also found that when AGL is missing or reduced, another enzyme, called HAS2, becomes more active. HAS2 makes a substance called hyaluronic acid (HA), which is known to help bladder tumors grow and spread. This means that AGL and HAS2 may be linked in a way that affects how bladder cancer develops. 

What This Research Proposes to Address 

To better understand this link, the researchers will test two main ideas:
First, they will study whether the combination of HAS2 and HA is the main reason tumors become more aggressive when AGL levels are low. Second, they will look at whether low levels of AGL in normal bladder tissue increase the risk of bladder cancer starting in the first place.

The research will also test possible treatment strategies that block this pathway to see if they could help patients with bladder cancer. 

Why This Research Is Important 

This study could help explain why some bladder cancers grow and spread more quickly than others. If AGL loss is confirmed as a risk factor, doctors could better predict which patients are more likely to develop bladder cancer or have aggressive disease.

Even more importantly, by targeting the HAS2/HA pathway, scientists may discover new treatment options for patients. This could lead to better ways to stop tumor growth and improve survival for people with bladder cancer. 

Final Report Summary

Our research is focused on how bladder cancer grows and spreads. We found that when a certain gene called AGL is missing, bladder cancer cells grow much faster. This happens because the loss of AGL activates a chain of signals—called the HAS2-HA-CD44/RHAMM pathway—that helps tumors become more aggressive. We also saw that blocking this pathway in different ways could open the door to new, personalized treatments for patients who have low levels of AGL. 

By studying patterns in both lab experiments and patient samples, we discovered that AGL and the other proteins in this pathway (HAS2, CD44, and RHAMM) all play connected but also unique roles in how bladder cancer behaves. 

To go further, we created special mice without the AGL gene. These models will allow us to see more clearly how bladder tumors start, grow, and spread. They will also help us test new treatment strategies. This work lays the foundation for finding better ways to treat bladder cancer, especially in patients with aggressive disease linked to low AGL levels. 

Oldenburg, D., Ru, Y., Weinhaus, B., Cash, S., Theodorescu, D., & Guin, S. (2016). CD44 and RHAMM are essential for rapid growth of bladder cancer driven by loss of Glycogen Debranching Enzyme (AGL). BMC cancer, 16(1), 713. https://doi.org/10.1186/s12885-016-2756-5

Guin, S., Ru, Y., Agarwal, N., Lew, C. R., Owens, C., Comi, G. P., & Theodorescu, D. (2016). Loss of Glycogen Debranching Enzyme AGL Drives Bladder Tumor Growth via Induction of Hyaluronic Acid Synthesis. Clinical cancer research : an official journal of the American Association for Cancer Research, 22(5), 1274–1283. https://doi.org/10.1158/1078-0432.CCR-15-1706

Ritterson Lew, C., Guin, S., & Theodorescu, D. (2015). Targeting glycogen metabolism in bladder cancer. Nature reviews. Urology, 12(7), 383–391. https://doi.org/10.1038/nrurol.2015.111

None Reported as of August 2025

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