Bladder Tumor Subtype Commitment Occurs in Carcinoma In-Situ Driven by Key Signaling Pathways Including ECM Remodeling

It is profound that despite years of intensive therapeutic efforts, a staggering 50-60% of patients with muscle-invasive urothelial bladder cancer will have a local or distant disease recurrence within five years with only limited therapeutic options. Therefore, it is imperative to understand how these tumors develop and continue efforts to identify new therapeutic targets. Because basal and luminal tumor subtypes of invasive bladder tumors have significant prognostic and predictive impacts for patients we sought to answer the question: When does subtype commitment occur and which signaling gene pathways are important during the process of tumorigenesis?

In our presently published paper,¹ we implemented a unique and powerful methodology whereby an entire excised bladder housing urothelium, precursor lesions, and different stages of carcinomas was globally mapped both histologically and molecularly using mRNA and protein analyses (whole organ bladder mapping). In addition, a separate cohort of patient-matched tissues comparing precursor lesions, mainly carcinoma in situ (CIS), with matching muscle-invasive tumors was analyzed.

The main message from our present manuscript is that the final stage of subtype commitment to a luminal or basal muscle-invasive tumor occurs at the transition from carcinoma in situ to invasive tumor stages. Interestingly, this transition is a complex transdifferentiation process where CIS frequently showed preserved expression of both, luminal and basal differentiation markers. However, marker expression of the final subtype occurring in MIBC was dominant in basal or luminal CIS, respectively. We further could demonstrate that aberrant staining patterns of luminal and basal immunohistochemistry markers are helpful to distinguish between luminal or basal CIS.

In addition to luminal and basal gene expression phenotypes our study brings forth novel findings that precursor lesions and tumor-associated urothelium share a similar gene expression, which we define as a "luminal extracellular matrix (ECM)/p53-like" gene expression phenotype. Normal urothelium from healthy non-cancer patients had significantly lower ECM-like gene expression, supporting an oncogenic field-affection of normal-appearing normal urothelium and a significant impact of the stromal tumor environment in tumor development and progression.

Investigating the luminal ECM-like expression phenotype further using a PanCancer Progression Panel of 681 genes revealed pathways specific for ECM remodeling, angiogenesis, epithelial to mesenchymal transition (EMT), cellular discohesion, cell motility supporting a strong role of these pathways in tumor progression already at the stage of normal-appearing tumor-associated urothelium. On the other hand, genes defining cell proliferation and oncogenic ERBB2/ERBB3 signaling were prominently upregulated in invasive bladder carcinomas.

We hope that our present study will be important for clinical translation with the hope and possibility of highlighting genes important for therapy targeting muscle-invasive carcinomas but also precursor lesions since especially CIS represents a challenging clinical diagnosis with high rates of recurrence and also progression to (muscle) invasive bladder carcinomas.

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