Molecular switch linked to cell lineage plasticity, therapy resistance: Newsroom

UT Southwestern researchers have identified a new mechanism involved in tumor cells. This 3D illustration shows findings that could lead to better treatments for prostate cancer, the most common cancer in men. (Photo credit: Getty Images)

DALLAS – June 4, 2024 – Two genes working in tandem play key roles in shaping the identity and behavior of prostate cancer cells and their response to treatment, researchers at UT Southwestern Medical Center report. Cancer Detectionprovides important insight into how cancer cells evade current standard treatments and offers a potential target for the development of new therapeutic approaches for prostate cancer.

Dr. Ping Mu is an assistant professor of molecular biology and a member of the Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern, and the Deborah and W. A. ​​“Tex” Moncrief, Jr. Scholar in Medical Research.

“Our study uncovers new genetic and molecular processes that control how tumor cells change type and respond to treatment,” said the study leader. Dr. Ping MuAssistant Professor Molecular Biology and Harold C. Simmons Comprehensive Cancer Center “These important discoveries improve our understanding of what drives drug resistance and introduce new approaches to treating prostate cancer,” the UT Southwestern researchers said in a statement.

One in eight men will develop prostate cancer in their lifetime, making it the most common cancer among men. American Cancer Society.

Prostate cancer's ability to adapt has proven to be a formidable challenge, with treatment resistance emerging as a major obstacle. Advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), is particularly difficult to treat due to its ability to acquire resistance to traditional therapies such as androgen receptor (AR) inhibitors.

This resistance may arise through lineage plasticity, which allows cancer cells to undergo an “identity switch” and evade targeted therapies. Lineage plasticity allows cancer cells to switch from their original luminal lineage, driven by androgen receptor (AR) signaling, to alternative lineages, such as neuroendocrine or stem-like phenotypes. These lineages are resistant to AR-targeted therapies originally designed to target their previous identity.

In this study, the researchers identified zinc finger protein 397 (ZNF397) is a key trigger of this transformation in prostate cancer cells. This defect changes the cell's dependence on AR signaling for proliferation (luminal lineage) to the loss of the gene Ten Eleven Translocation 2 (Tet 2) encodes an enzyme that controls DNA methylation, a key epigenetic mechanism. This transition makes cancer cells more flexible and adaptable, and ultimately resistant to therapies targeting AR signaling.

In this study, Tet 2 This study promotes epigenetic rewiring, contributing to lineage plasticity and therapeutic resistance in prostate cancer, and elucidates how prostate cancer cells adapt through epigenetic reprogramming. Tet 2 Resistance to AR-targeted therapy can be reversed ZNF397By genetic and pharmacological inactivation Tet 2The researchers effectively reversed resistance to AR-targeted therapy. ZNF397Missing tumor.

This study Mu-LabWe will improve our understanding of the mechanisms of cell lineage plasticity and drug resistance, paving the way for personalized therapeutic strategies to combat cell lineage plasticity-induced therapeutic resistance in prostate cancer.

“The possibility of reversing this kind of resistance is Tet 2 “Combining drugs opens new avenues for developing treatments for men with advanced prostate cancer,” Dr. Mu said. “These findings may lead to testing of prostate cancer treatments in clinical trials.” Tet 2 “Inhibitors are being used to treat patients with metastatic castration-resistant prostate cancer, with the potential to improve outcomes and increase survival rates.”

Other UTSW researchers who contributed to the study include Ganesh V. Raj, M.D., professor; Urology and PharmacologyCarlos L. Arteaga, MD, Professor, Simmons Cancer Center Ariella B. Hunker, PhD, associate dean of the Oncology Program, Simmons Cancer Center and Tao Wang, PhD, assistant professor of medicine; Peter O'Donnell Jr. School of Public Health And that Center for Genetics of Host Defense; Su Deng, PhD, Lecturer in Molecular Biology; postdoctoral researchers Yaru Xu, PhD, Xiang Li, PhD, Xiaoling Li, PhD, and Quanhui Xu, PhD; and graduate student researchers Yuqiu Yang, MSc, Choushi Wang, BSc, Julisa Gonzalez, BSc, Atreyi Mukherji, BSc, Carla Rodriguez-Tirado, BSc, Mia Hofstad, BSc, Yuyin Jiang, BSc (Research Technician), and Lauren A. Metang, MSc (Senior Research Associate).

Dr. Moo is the Deborah and W.A. “Tex” Moncrief Jr. Scholar in Medical Research at UTSW.

This work was funded by grants from the National Cancer Institute/National Institutes of Health (5R00CA218885 and 1R37CA258730, 1R01CA258584, T32C124334, 1F31CA261019-01A1), the U.S. Department of Defense (W81XWH-18-1-0411 and W81XWH21-1-0520, W81XWH21-1-0418), the Texas Cancer Prevention and Research Institute (RR170050, RP220473, RP230363), the Prostate Cancer Foundation (17YOUN12 and 21YOUN10), the Welch Foundation (I-2005-20190330), a UT Southwestern Harold C. Simmons Comprehensive Cancer Center Pilot Award, and the Simmons Cancer Research Foundation. the Center for Data Science Shared Resources, a Terry Fox New Frontiers Program Project Grant (PPG19-1090), a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543), and the Life Sciences Research Foundation.

Disclosures are included in the study.

About UT Southwestern Medical Center

UT Southwestern is one of the nation's leading academic medical centers, integrating pioneering biomedical research with outstanding clinical care and education. The university's faculty has won six Nobel Prizes and includes 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute investigators. The university's more than 3,100 full-time faculty members are responsible for groundbreaking medical advances and are committed to rapidly translating science-based research into new clinical care. UT Southwestern physicians across more than 80 specialties provide more than 120,000 inpatient and 360,000 emergency care visits, and approximately 5 million outpatient visits annually.