New York City, April 20, 2022 Scientists at Memorial Sloan Kettering Cancer Center (MSK) have hinted at never-before-seen details about the human androgen receptor — the protein inside cells that responds to typical male hormones such as testosterone. Their research was published on April 20, 2022 in the journal molecular cellidentifies the receptor’s unique features that distinguish it from other hormone receptors and provides clues to how androgen signaling is skewed in prostate cancer.
“We know a lot about androgen receptors from studies at a level of about 10,000 feet,” says Charles Sawers, head of the Human Oncology and Pathogenesis Program at MSK that researches the biology and treatment of prostate cancer. “But to get closer to the real event, you have to get down to the atomic level, and we were able to get much closer to that goal with this study.”
To get this closer, Dr. Sawers partnered with Elizabeth Wasmut, a structural biologist who has done graduate work at the Sloan Kettering Institute and is now doing a joint postdoctoral fellowship at MSK and Rockefeller University. Dr. Wasmut has experience using cryoEM microscopy to study the atomic details of molecules and is interested in using this knowledge to solve long-standing problems in cancer biology.
“People have been trying for years to get structural data for the androgen receptor, but it has been very difficult,” Dr. Wasmut says. “Basically, for this study, we had to throw the entire kitchen sink on it.”
One of the biggest challenges was the fact that androgen receptors per se do not dissolve easily in solution, a prerequisite for being able to use cryoEM to visualize this. Instead, the receptor clumps remain stuck together in a kind of “ball of mucus,” says Dr. Sawers.
What he calls his “eureka moment” came when they added another protein to the mix – a known cancer-causing protein called ERG. Just like that, the group was put into solution. “Suddenly we had something to look at,” he says.
There are still many challenges to overcome, and researchers have had to be resourceful. In addition to MSK’s cryoEM, the team also relied on cryoEM devices at the New York Center for Structural Biology, Rockefeller, and the Janelia Campus of the Howard Hughes Medical Institute.
New interpretations of old notes
The androgen receptor is the so-called nuclear hormone receptor. It moves between the cell’s cytoplasm and the nucleus, where it turns on genes that maintain typical male traits. The traditional model for how nuclear hormone receptors work is that they essentially form two major forms. One form predominates when the receptor is inactive and is released into the cytoplasm; The other form forms after the hormone androgen binds to it. This duplication then travels to the nucleus, where it binds to DNA and turns on genes. This is the well-known way that estrogen receptors work, for example.
By contrast, cryoEM images obtained by Dr. Wasmuth showed that androgen receptors were more flexible into the shapes they could form. In particular, it can form different DNA-binding motifs, enabling it to turn on a wide range of genes, depending on what conformation it was in – something we haven’t seen before in this group of receptors.
“Androgen receptors don’t follow the rules,” says Dr. Wasmut.
The different 3D shapes created by these movements also allow the androgen receptors to interact with other proteins that change their shape – so-called allosteric interactions. One of the proteins it can interact with in this way is ERG, a major driver of prostate cancer.
This ability to change shape helps explain some of the older observations about androgen hormones, including the fact that they play many roles in development and puberty. The androgen receptor is simply more diverse in the combinations of genes it can turn on than other nuclear receptors. Indeed, recent findings suggest that it can influence T-cell responses to immunotherapy.
What is next for this research?
While the images they collected of the androgen receptor are the most detailed to date, the researchers hope to improve these results, by moving to a deeper atomic resolution. Once they do, it may be reasonable to consider designing drugs to block certain movements of the androgen receptor — to prevent its interaction with the ERG, for example.
Scientists say the ability to conduct such interdisciplinary studies, where scientists from different fields can collaborate closely, is a unique feature of MSK’s research environment, including the Sloan Kettering Institute and Rockefeller University.
“It speaks to the culture and community in the amazingly rich research triangle here on 68th Street,” says Dr. Sawers.
“I don’t really think this work can be done anywhere else, to be honest,” Dr. Wasmut adds.
This research was supported by Memorial Cancer Center Cryo-EM Cryo-EM with funding from NCI Cancer Center Support Grant P30-CA008748, Department of Defense under award number W81XWH-18-1-0182, Prostate Cancer Foundation Young Investigator Award, National Institute of Science General Medical Center of the National Institutes of Health under award number K99 GM140264, Howard Hughes Medical Institute, and the National Cancer Institute. Dr. Sawers serves on the Novartis board of directors, is a co-founder of Oric Pharma and co-inventor of enzalutamide and apalutamide. He is a scientific advisor to Arsenal, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ and PMV.
About Memorial Sloan Kettering Cancer Center (MSK):
As the oldest and largest private cancer center in the world, Memorial Sloan Kettering Cancer Center has dedicated more than 135 years to exceptional patient care, impactful educational programs, and innovative research to discover more effective strategies to prevent, control, and ultimately treat cancer. MSK is home to more than 20,000 doctors, scientists, nurses, and staff united by an relentless dedication to conquering cancer. Today, we are one of 52 National Cancer Institute-designated comprehensive cancer centers, with the latest science and technology supporting pioneering clinical studies, personalized treatment, and compassionate care for our patients. We also train the next generation of clinical and scientific leaders in oncology through our ever-evolving educational programs here and around the world. Year after year, we are ranked among the top two cancer hospitals in the country, consistently recognized for our expertise in adult and pediatric oncology specialties. www.mskcc.org.
The date the article was published
April 20 2022