Research to elucidate the origin and progression of bladder cancer

A study led by researchers at Weill Cornell Medical Institute and the New York Genome Center sheds new light on how bladder cancer begins and progresses. Researchers have found that an antiviral enzyme that mutates the DNA of normal and cancer cells is a key driver of early bladder cancer development, and that standard chemotherapy is also a strong cause of mutations. . Researchers also discovered that an overactive gene within an abnormal circular DNA structure of a tumor cell gene causes bladder cancer to be resistant to treatment. These findings provide new insights into the biology of bladder cancer and suggest new therapeutic strategies for this difficult-to-treat cancer.

The study, published Sept. 9 in Nature, focused on urothelial carcinoma, the main form of bladder cancer. Urothelial cancer originates from the cells that line the tubes that drain urine from the bladder, urethra, and kidneys. The researchers examined malignant and pre-malignant urothelial cells from the same group of patients at different stages of the disease. They used whole-genome sequencing and advanced computational techniques to map common DNA mutations, complex structural variations, and their timing.

“Our findings reveal a new fundamental mechanism that drives bladder cancer progression, a mechanism that can now be considered for targeting with therapeutics.” said senior author Bishoy Faltas, Ph.D., Gellert Family and John P. Leonard, M.D., Fellow in Hematology and Medical Oncology. Associate Professor of Medicine and Cell and Developmental Biology at Weill Cornell Medicine and Oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Dr. Nicholas Robin, Director of Computational Biology at the New York Genome Center, and Dr. Olivier Element, Director of the Englander Institute for Precision Medicine and Professor of Physiology and Biophysics at Weill Cornell Medical College, also worked with Dr. Faltas on the study. led. . Co-first author was Duy Nguyen, a technician at the Faltus Institute (currently a doctoral student at Harvard Medical School). William Hooper, bioinformatics scientist at the New York Genome Center; Dr. Weisi Liu, a lecturer in the Faltas lab.

Focus on key therapeutic targets

Approximately 80,000 cases of bladder cancer occur annually in the United States. If caught early, it can be cured with surgery, but approximately 30% of cases are diagnosed at a later stage, making successful treatment much more difficult.

Researchers in a new study found strong evidence that the APOBEC3 enzyme causes early mutations that may trigger the development of this type of cancer. These enzymes evolved to disable retrovirus infection by editing viral DNA, but they are known to sometimes mutate a cell's own DNA.

“It is not yet clear what role mutations caused by APOBEC3 play in cancer development,” said David E., principal investigator at the Englander Institute for Precision Medicine and Sandra Edward Meyer Cancer Center. said Dr. Faltas, who is also a member of the Weill Cornell Medicine. “But we now know that these mutations appear early in urothelial cancer and also occur in precancerous urothelial tissue.” focuses on the study of the role of mutagenic enzymes.

Researchers found that cisplatin and other platinum-based chemotherapy induce more prominent mutations, some of which may increase the survival rate of urothelial cancer cells and allow them to metastasize despite treatment. I discovered that.

The third major finding was that urothelial tumors often contain complex rearrangements of DNA that give rise to circular segments of DNA. These “extrachromosomal DNAs” (ecDNAs) reside separate from the chromosomes in the cell nucleus and can carry hundreds of copies of the proliferative genes that drive cancer. Researchers found that these ecDNA events persist and become more complex after treatment, incorporating new DNA segments, suggesting that these events are driving resistance to treatment. .

This led the team to ly model an ecDNA version of one of these genes. CCND1, Master regulator of the cell cycle in the laboratory. The results of these experiments confirmed the following: CCND1 This extrachromosomal structure increases treatment resistance.

Taken together, this finding paints a clearer picture of the factors that cause and drive urothelial cancer.

“Traditionally, when analyzing tumor genomes, we have used methods that analyze only a small portion of a tumor's DNA, but if we sequence all of the DNA and evaluate it in smart ways, we can discover much more. I realized what I could do: data,” Dr. Element said. “I think this collaboration supports that strategy.”

Researchers at the Englander Institute and the New York Genome Center are planning a large-scale collaboration in the future to delve deeper into the biology of urothelial cancer. For example, whole-genome sequencing of DNA with readouts of gene activity in individual tumors as well as bulk tumor samples. cell.

“If we can combine these two pieces of information at the single-cell level, it will be very important and interesting,” Dr. Robin said.

The researchers also plan to study potential clinical applications of this work. Researchers have discovered that a new FDA-approved drug ERBB2 The HER2 receptor protein, a gene product also present in breast cancer cells, works particularly well in patients with strong symptoms of urothelial cancer. ERBB2 ecDNA. They are also working on finding ways to block the formation and maintenance of ecDNA.