Protein Network Mapping of Bladder Cancer: An Analysis of Tumor Compartment and the Surrounding Microenvironment



Hodge, K Alex

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The interaction between tumor and stroma has become of intense interest in the field of oncology in order to better understand the driving forces behind tumor onset and progression, metastasization and the responsiveness to therapy. These interactions are hard to capture using in vitro techniques and the extent to which in vivo models really recapitulate the tumor-stroma interactions of human tissues is still under investigation. For these reasons, human specimens still remain optimal input material for exploring these interactions. Laser capture microdissection (LCM) coupled with reverse phase protein microarrays (RPPA) are ideal technologies for isolating different cell compartments from heterogeneous tissues and for exploring protein signaling network of human tissue specimens. This study explored the protein signaling network of 23 bladder cancer samples within the epithelium and the surrounding stroma across different histotypes including normal, carcinoma in situ (CIS), papillary, and invasive cellular compartments. Pure tumor epithelium and surrounding stroma from each sample were first isolated with LCM followed by RPPA that allows for the measurement of hundreds of proteins and phosphoproteins. The analysis of the epithelium compartments collected from patients affected by invasive and non-invasive (papillary) bladder cancer revealed different pathway involvement driving the tumor, with invasive cases showing a phenotype of immune/ inflammation, proliferation and survival in contrast to papillary tumors which were characterized by wound healing and metabolism. While the stroma surrounding both invasive and papillary tumors showed high correlation between the different members of the PI3K/AKT pathway, only invasive tumors presented with interconnection between proteins involved in the immune/ inflammation response. Receptor tyrosine kinases (RTKs) in the epithelium appeared to be highly correlated with RTKs in the stroma as well as their downstream targets suggesting a cross-talk between the two compartments. Finally, programmed death ligand 1 (PD-L1), an important drug target immune checkpoint protein, was increased significantly in invasive epithelium when compared to papillary epithelium. This PD-L1 expression offers a promising therapeutic target against invasive bladder cancer, which has had minimal treatment advances in more than a decade.



Cancer, Bladder, Arrays, Immunotherapy, Stroma, PD-L1