Bladder cancer is one of the most common cancers worldwide, but what many people don’t realise is that it’s not a single, uniform disease. Among the various types, histologic variant (HV) bladder cancers stand out as especially rare, aggressive, and difficult to treat. A recent study Heiko Yang et al, published on 17th June, has revealed new insights into these challenging cancers:
“Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression”
https://pubmed.ncbi.nlm.nih.gov/40527915
The results of this research have opened new doors to our understanding of the molecular underpinnings of HV bladder cancers, and may also pave the way for more precise, targeted treatments.
Overview of Bladder Cancer
Bladder cancer primarily arises from the urothelial cells lining the inside of the bladder, which is why the most common type is called urothelial carcinoma (UC). According to global statistics, bladder cancer affects over half a million people each year, with varying outcomes depending on stage, grade, and type. UC makes up around 75% of cases, leaving the remaining 25% classified as histologic variants. While UC has established treatment protocols including surgery, chemotherapy, and immunotherapy, HV bladder cancers present unique challenges that often render standard approaches ineffective.
Histologic Variant (HV) Bladder Cancers – Rare and Dangerous
HV bladder cancers include subtypes like micropapillary, plasmacytoid, sarcomatoid, and nested variants, each with distinct histologic appearances under the microscope. What they share, unfortunately, is a reputation for aggressive behaviour – invading deeper tissue layers, spreading faster, and resisting conventional treatments. Patients diagnosed with HVs tend to have poorer survival rates, and oncologists struggle with both diagnosis and management due to the lack of reliable biomarkers and targeted therapies.
Until now, little was known about what drives this aggressive behaviour at the molecular level. While pathologists can identify HVs under the microscope, there has been a pressing need to discover molecular markers that can guide treatment decisions, predict prognosis, or help monitor disease progression.
Compared to standard UC, HVs are more likely to present at an advanced stage, involve muscle-invasive disease, and metastasise early. They also show poor responses to chemotherapy and immunotherapy, frustrating patients and clinicians alike. One reason for this may be that HV tumours harbour unique cell populations or signalling pathways that allow them to evade treatments designed for UC.
The New Breakthrough Study
Yang and his colleagues took an innovative approach to tackle the mystery of HV bladder cancers. By applying single-cell RNA sequencing (scRNA-seq) to analyse tumour samples, they were able to study the gene expression of individual cancer cells rather than averaging out data from bulk tissue. This approach allows researchers to identify rare or hidden cell populations that might drive disease progression or resistance.
The study analysed samples across multiple HV subtypes and compared them with pure UC tumours. Their goal was to uncover shared molecular features that could explain why HVs are so aggressive and to find potential targets for therapy.
Key Findings
Among the many insights, one of the most striking was the discovery of a distinct cluster of cancer cells – labelled Cluster 13 – that appeared consistently across several HV subtypes. This cluster was characterised by the expression of CA125, a protein more commonly associated with ovarian and pancreatic cancers. Not only were CA125+ cells found in primary tumours, but they were also present in metastatic lesions, suggesting they play a central role in driving the disease.
Discovery of Cluster 13: The CA125+ Cell Population
The identification of Cluster 13 is a game-changer in the HV bladder cancer field. These CA125-expressing cells appear to represent a shared, aggressive cell state across multiple HV subtypes. CA125, also known as MUC16, is a well-known cancer antigen that’s been used for years to monitor ovarian cancer, particularly in assessing treatment response and detecting relapse.
That CA125 shows up so prominently in HV bladder cancers is both surprising and promising. It raises immediate questions: Could CA125 be used to diagnose HV bladder cancers earlier? Could it help track disease progression or predict patient outcomes? And perhaps most importantly, could therapies that target CA125 or its related pathways offer new hope to patients?
CA125 Presence in Primary and Metastatic HV Tumours
What makes this finding even more significant is that CA125+ cells were found not just in primary tumours, but also in metastatic sites. This suggests that CA125 may mark a particularly invasive and resilient cell population – the kind that escapes the bladder and seeds new tumours elsewhere. For clinicians, having a blood biomarker like CA125 that reflects tumour burden could transform how they monitor patients with HV bladder cancer.
How CA125 Levels Differ Between HV and UC Patients
Yang et al. didn’t stop at cell-level findings. They also looked at serum CA125 levels in patients and found that those with HV bladder cancers had significantly higher levels compared to those with pure UC tumours. This difference could be clinically meaningful. Currently, there are no established serum biomarkers for bladder cancer, unlike prostate-specific antigen (PSA) for prostate cancer. The possibility that CA125 could fill this gap for HV bladder cancer is exciting.
