Why does losing the Y chromosome make some cancers worse? New $6.5 million NIH grant could provide clues

(Press-News.org) TUCSON, Ariz. — University of Arizona Cancer Center researchers will study the potential effects of the loss of the Y chromosome in the development and progression of bladder cancer thanks to a grant of up to $6.5 million over seven years from the National Cancer Institute.

Dr. Dan Theodorescu, the Nancy C. and Craig M. Berge Endowed Chair for the Director of the Cancer Center, was awarded the NCI Outstanding Investigator Award, which is given to allow “substantial time for funded investigators to take greater risks and be more adventurous in their research,” according to the NCI.

Theodorescu’s goal is to better understand the biology of Y chromosome loss with an eye toward prevention, early detection and treatment approaches for bladder and other cancers.

Theodorescu has made pioneering discoveries about the potential effects of the loss of the Y chromosome on the development of cancer, as well as the immune system. He and his team have shown that bladder cancer was more aggressive in men lacking the Y chromosome in cancer cells.

“The clinical relevance of losing the Y chromosome offers new and untapped opportunities to understand cancer development and progression, and gain insights into cancer treatment vulnerabilities,” said Theodorescu, professor of urology at the College of Medicine – Tucson. “We’d like to understand the mechanisms that make cancer cells more aggressive when they lose the Y chromosome and explore why there is a connection between the loss of Y in cancer cells and the comparable loss in immune cells.”  

In males, each cell in the body usually contains one X and one Y chromosome. Losing the Y chromosome in immune cells in the blood is a common, nonhereditary genetic change in men that is often associated with aging. It also has been associated with increased risk of death from cancer or cardiac disease yet why this happens has been unclear.

Earlier this year, Theodorescu and his team explained for the first time how losing the Y chromosome in immune cells could affect immune system function. They showed that cells lacking the Y chromosome make the immune system less effective in fighting the cancer, suggesting why the loss of Y is associated with lower cancer survival rates.

With the help of the new funding, Theodorescu will use stem cell and mouse models to better understand the effects of losing the Y chromosome in bladder cancer and immune cells. More specifically, he and his team will compare how losing the Y chromosome in T cells – immune cells that help fight off cancer – affects the growth of genetically engineered mouse and human bladder cancer cells. They also plan to study what happens to cancer growth when individual genes from the Y chromosome are blocked.

“I think we’re going to discover some new information about the roughly 100 genes on the Y chromosome and the roles they play, including if they provide any therapeutic insights,” he noted. 

Theodorescu also plans to screen thousands of compounds, including approved and investigational drugs, in unique mouse and human bladder cancer models to identify possible effects on tumors lacking the Y chromosome. 

One of the areas he has already begun to explore is the correlation between loss of Y chromosome in tumor cells and the loss of Y in the tumor microenvironment, the ecosystem of immune cells, normal cells, blood vessels and more that surrounds and interacts with the cancer. 

“The Y chromosome cancer biology is like an undiscovered country,” he said. “While our findings on the Y chromosome and cancer appear significant, the real impact will be if we can help patients.”

That might mean finding ways to prevent or diminish the effects of losing the Y chromosome or developing a treatment that could disarm cancer cells missing the chromosome. He also would like to examine how the loss of Y in cancer cells and immune cells could affect patient responses to chimeric antigen receptor, or CAR, T-cell therapy, a personalized form of immunotherapy mostly used for blood cancers.

While his group’s current platform and models are mostly on bladder cancer, he plans to extend and generalize the work across other cancer types.

“This grant is giving us the opportunity to do what we hope will become foundational biological research,” Theodorescu said. “We hope these observations can be translated to the clinic and add a novel dimension to our fundamental understanding of cancer.”

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