Researchers at Weill Cornell Medicine have performed the most comprehensive analysis to date of cancer of the ureters or the urine-collection cavities in the kidney, known as upper tract urothelial carcinoma (UTUC).  The study, which compared the characteristics of primary and metastatic tumours, provides new insights into the biology of these aggressive cancers and potential ways to treat them.

In the study, which appeared in Nature Communications, the researchers examined tissue samples from 44 primary and metastatic UTUC tumours. They compared gene mutations and gene activity patterns in these tumours and mapped cell types using a technology that can visualise protein surface markers at the single-cell resolution. A key finding was that the basic molecular characteristics of these UTUC tumours—their molecular subtype—are mostly stable during the evolution from the primary to the metastatic stage. That suggests that oncologists treating UTUC patients may often be able to use analyses of primary tumour samples for molecular subtype-guided treatment of metastases.

“This dataset we generated provides unique insights into UTUC biology and should be an important resource for researchers and clinicians,” said Dr. Juan Miguel Mosquera, a professor of pathology and laboratory medicine and director of research pathology in the Englander Institute for Precision Medicine at Weill Cornell Medicine.

Dr. Mosquera, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, co-led the study with Dr. Bishoy Faltas, an assistant professor of medicine and the Gellert Family-John P. Leonard, M.D. Research Scholar at Weill Cornell Medicine. The study’s first author is Dr. Kentaro O’Hara, who was a postdoctoral research fellow in the Department of Pathology and Laboratory Medicine and in the Englander Institute for Precision Medicine when the study was conducted.

UTUC tumours are rare compared to bladder tumours, accounting for 5 to 10 percent of all urothelial cancers. They are also considered relatively aggressive, and metastatic UTUC tumours are particularly hard to treat successfully. Previously, Dr. Faltas and colleagues illuminated the molecular details of primary UTUC tumours in a widely cited 2019 study. Much less has been known about the characteristics of metastatic tumours that have already spread to distant organs.

Building on this work, the researchers used DNA and RNA sequencing in the current study to map the gene mutations and gene activity patterns in the primary and metastatic samples. With funding from the Cornell Center for Immunology, they also employed a newer technique called Imaging Mass Cytometry. This technique labels key surface proteins on individual cells in the samples, enabling detailed, cell-by-cell identification and spatial mapping of cell types.

“The Imaging Mass Cytometry allowed us for the first time to explore the spatial relationships between tumour cells and other cells such as immune cells that make up the UTUC tumour microenvironment,” said Dr. Mosquera, who is also a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The 2019 study led by Dr. Faltas revealed that primary UTUC tumours usually belong to a particular molecular subtype that also features a relative absence of T cells—suggesting immune suppression in the tumour microenvironment. The new analysis confirmed this pattern and found that metastatic UTUC tumours in a given patient tended to have the same characteristics as the primary tumour.

“Frequently, we are unable to obtain sufficient biopsy tissue from metastatic tumours and have to rely on the molecular analysis of the primary tumour, so it’s important to know that the molecular subtype based on RNA expression is generally stable from the primary to the metastatic stages,” said Dr. Faltas, who is also director of bladder cancer research in the Englander Institute for Precision Medicine and a member of the Meyer Cancer Center at Weill Cornell Medicine, and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. “We were able to understand the contributions of different cell types to these molecular subtypes and how they evolve over the cancer’s natural history by analysing the protein expression of hundreds of thousands of single cells from these tumours.” 

The researchers also observed that metastatic UTUC tumour cells had genetic mutations not found in the primary tumours. These differences were much greater in patients undergoing chemotherapy, suggesting that chemotherapy may have induced some mutations.

The study sets the stage for highly personalised, molecularly-guided primary and metastatic UTUC treatment strategies to improve patient outcomes. The single-cell insights gained have the potential to accelerate the development of targeted therapies and immunomodulatory approaches and transform the landscape of UTUC management.

Research reported in this story was supported by the National Cancer Institute of the National Institutes of Health under award number T32CA203702. The research was also supported by funding from the Starr Cancer Consortium.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Juan Miguel Mosquera and Dr. Bishoy Faltas.

Source: Weill Cornell Medicine