Researchers found that DNA mutations from antiviral enzymes and chemotherapy fuel early bladder cancer, while abnormal circular DNA in tumor cells drives resistance to therapy. These discoveries open new therapeutic avenues.
A groundbreaking study led by researchers at Weill Cornell Medicine and the New York Genome Center has provided unprecedented insights into how bladder cancer begins and progresses. The team discovered that antiviral enzymes, which mutate the DNA of both normal and cancer cells, are key promoters of early bladder cancer development, and that standard chemotherapy is also a potent source of mutations.
The researchers also discovered that overactive genes within abnormal circular DNA structures in tumor cells genes drive bladder cancer resistance to therapy. These findings are novel insights into bladder cancer biology and point to new therapeutic strategies for this difficult-to-treat cancer.
The study, published recently in Nature, focused on the main form of bladder cancer, urothelial carcinoma, which originates from cells that line the bladder, urethra, and tubes that drain urine from the kidneys. The researchers examined malignant and pre-malignant urothelial cells taken from the same set of patients at different disease stages. They used whole-genome sequencing and advanced computational methods to map common DNA mutations, complex structural variants, and their timing.
“Our findings define new fundamental mechanisms driving bladder cancer evolution—mechanisms that we can now think about targeting with therapies,” said co-senior author Dr. Bishoy Faltas, the Gellert Family–John P. Leonard MD Research Scholar in Hematology and Medical Oncology and an associate professor of medicine and of cell and developmental biology at Weill Cornell Medicine, and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Dr. Nicolas Robine, director of computational biology at the New York Genome Center, and Dr. Olivier Elemento, director of the Englander Institute for Precision Medicine and a professor of physiology and biophysics at Weill Cornell Medicine, also led the study with Dr. Faltas. The co-first authors were Duy Nguyen, a technician in the Faltas Laboratory (now a doctoral student at Harvard Medical School); William Hooper, a bioinformatics scientist at the New York Genome Center; and Dr. Weisi Liu, an instructor in the Faltas Laboratory.
Major Therapeutic Targets Come into Focus
Bladder cancer occurs at the rate of about 80,000 cases per year in the United States. It can be cured with surgery if caught early, but about 30 percent of cases are diagnosed at later stages when it is much harder to treat successfully.
The researchers in the new study found strong evidence that the APOBEC3 enzymes cause early mutations that may help trigger the development of this cancer type. These enzymes evolved to disable infecting retroviruses by editing their viral DNA, though it is known that they can sometimes mutate cells’ own DNA.
“The exact role of APOBEC3-induced mutations in cancer initiation hasn’t been clear,” said Dr. Faltas, who is also the chief research officer at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “But we found that these mutations appear early in urothelial cancer, occurring even in pre-malignant urothelial tissue.” In his lab, Dr. Faltas is focusing on studying the role of these mutagenic enzymes in driving cancer evolution.
The researchers found that cisplatin and other platinum-based chemotherapies cause further prominent bursts of mutations, some of which likely allow urothelial cancer cells to survive better and spread despite treatment.
A third major finding was that urothelial tumors often contain complex rearrangements of their DNA that give rise to circular segments of DNA. These “extra-chromosomal DNAs” (ecDNAs) exist apart from chromosomes in the cell nucleus and can sometimes harbor hundreds of copies of cancer-driving growth genes. The researchers discovered that these ecDNA events persist and become more complex, incorporating new DNA segments after treatment, suggesting that they drive resistance to therapy.
This prompted the team to experimentally model an ecDNA version of one of these genes, called CCND1, a master regulator of the cell cycle in the laboratory. The results of these experiments confirmed that CCND1 in this extrachromosomal configuration drives treatment resistance.
Altogether, the findings paint a much clearer picture of the factors that trigger and drive urothelial cancer.
“Traditionally, when analyzing tumor genomes, we’ve used methods that analyze only a tiny fraction of their DNA, but we’ve come to realize that there’s a lot more to discover if we sequence all their DNA and use smart methods to evaluate that data,” Dr. Elemento said. “I think this collaboration vindicates that strategy.”
The Englander Institute and New York Genome Center researchers are planning larger future collaborative studies to dig even deeper into urothelial cancer biology, for example, doing whole-genome sequencing of DNA along with readouts of gene activity not just in bulk tumor samples but in individual tumor cells.
“Combining those two sets of information at the single-cell level would be tremendously important and interesting,” Dr. Robine said.
The researchers also plan to study potential clinical applications of this work. The investigators are hopeful that a new FDA-approved drug targeting the ERBB2 gene product—the HER2 receptor protein, also found on breast tumor cells—will work especially well in urothelial cancer patients with strong signs of ERBB2 ecDNAs. They are also working on finding ways to block ecDNA formation and maintenance.
Reference: “The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution” by Duy D. Nguyen, William F. Hooper, Weisi Liu, Timothy R. Chu, Heather Geiger, Jennifer M. Shelton, Minita Shah, Zoe R. Goldstein, Lara Winterkorn, Adrienne Helland, Michael Sigouros, Jyothi Manohar, Jenna Moyer, Majd Al Assaad, Alissa Semaan, Sandra Cohen, Florencia Madorsky Rowdo, David Wilkes, Mohamed Osman, Rahul R. Singh, Andrea Sboner, Henkel L. Valentine, Phillip Abbosh, Scott T. Tagawa, David M. Nanus, Jones T. Nauseef, Cora N. Sternberg, Ana M. Molina, Douglas Scherr, Giorgio Inghirami, Juan Miguel Mosquera, Olivier Elemento, Nicolas Robine and Bishoy M. Faltas, 9 October 2024, Nature.
DOI: 10.1038/s41586-024-07955-3
The research reported in this story was supported in part by the National Cancer Institute and the National Center for Advancing Translational Science, both part of the National Institutes of Health, through grant numbers R37CA279737, U01CA260369, UL1TR002384; and the United States Department of Defense through grant number W81XWH-17-1-0539. Additional support was provided by the Starr Cancer Consortium, the Leo & Anne Albert Institute for Bladder Cancer Care and Research, the Translational Research Program in the Department of Pathology and Laboratory Medicine at Weill Cornell Medicine, and the New York Genome Center’s Polyethnic-1000 Initiative.
News
Nanodiscs: What Are They and How Are They Shaping the Future of Medicine?
Nanodiscs are synthetic phospholipid particles with a distinct morphology and size that enhance their efficiency in drug delivery applications.1 First developed by Sligar et al. in the early 2000s, these model membrane systems measure around 10 [...]
New Discovery Reveals How Ovarian Cancer Starves Immune Cells
Researchers discovered that ovarian tumors hinder T cells’ energy supply by trapping a key protein, blocking lipid uptake. A new approach to reprogram T cells could enhance immunotherapy for aggressive cancers. Researchers at Weill Cornell [...]
Innovative Drug-Design Strategies to Overcome Antibacterial Resistance
Antibacterial resistance occurs when antibiotics fail to treat bacterial infections. This incidence is considered one of the top global health threats, stemming from the misuse or overuse of antibiotics in humans and animals.1 The [...]
Team introduces a cost-effective method to redesign search engines for AI
The internet search engine of the future will be powered by artificial intelligence. One can already choose from a host of AI-powered or AI-enhanced search engines—though their reliability often still leaves much to be [...]
Experiments demonstrate precise delivery of nanoparticles to lung
In recent years, bio-medical engineers have been developing promising techniques that could help diagnose diseases or precisely target specific regions inside the human body. Among these promising therapeutic strategies are methods that rely on [...]
What is Lassa fever? Everything to know about Ebola-like virus
Lassa fever has reached the US for the first time in a decade, in a case that has surprised health officials. The middle-aged patient in Iowa, who was not identified, died a 'short time' after being hospitalized [...]
Harvard Study Links Popular Plastic Ingredient to DNA Damage
Phthalate affects egg formation in C. elegans, resulting in abnormal chromosome numbers. A recent study conducted on roundworms has discovered that a common plastic ingredient can cause DNA strand breaks, leading to egg cells with an abnormal [...]
New research finds that subtle eye movements optimize vision
Our ability to see starts with the light-sensitive photoreceptor cells in our eyes. A specific region of the retina, termed fovea, is responsible for sharp vision. Here, the color-sensitive cone photoreceptors allow us to [...]
Scientists Were Wrong: Plants Absorb 31% More CO2 Than Previously Thought
New research shows plants absorb 31% more CO2 than previously estimated, raising the global GPP to 157 petagrams per year. Using carbonyl sulfide as a proxy for photosynthesis, this study highlights tropical rainforests’ critical role [...]
Doctors test first mRNA vaccine against norovirus
According to the Robert Koch Institute (RKI), the norovirus, which is widespread worldwide, is the cause of a large proportion of gastrointestinal infections. Those who catch the virus suffer from nausea, diarrhea and vomiting. [...]
Study reveals resistance of Pseudomonas aeruginosa to common cleaning agents
A new study reveals widespread resistance of a major bacterial pathogen to the active ingredients in cleaning agents commonly used in hospitals and homes. The American Chemical Society Infectious Diseases published the research, led [...]
AI’s Next Frontier: System 0 and the Future of Human Thought
“System 0” represents an emerging cognitive tool powered by AI that works alongside human intuition and analysis to enhance cognitive abilities. This new system promises to support complex decision-making and problem-solving but requires careful [...]
The Global Nanomedicine Market: Key Players and Emerging Technologies in Healthcare
This article provides an overview of the global nanomedicine market, highlighting key players, emerging technologies, and the challenges and opportunities that influence its growth and commercialization in the healthcare sector. Nanomedicines are nanotechnology-based drug products [...]
Scientists Have Discovered Toxic “Forever Chemicals” in Bottled Water
Scientists have found toxic PFAS in drinking water samples from around the world, with higher levels in tap water from China compared to the UK. Boiling water or using a filtration jug can reduce [...]
Urban Microbes Are Eating Disinfectants – Are We Fueling a New Health Threat?
New research reveals that microbes in urban environments are evolving to withstand the very cleaning agents designed to eliminate them. The study also uncovers new strains in Hong Kong, previously only found in the [...]
Startling Study Shows High-Potency Cannabis Alters DNA
The study shows that frequent use of high-potency cannabis alters DNA, affecting genes related to energy and immune function. These changes differ between those with and without psychosis, suggesting cannabis use could influence mental health through biological [...]