Mechanism of Action and Determinants of Response to BCG therapy in Bladder Cancer

BCG infection of bladder cancer cells -- Shown is a fluorescent image of BCG expressing green fluorescent protein infecting the bladder cancer cell line UMUC3

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is widely administered as a vaccine for tuberculosis. BCG is also used as a biotherapy for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, the mechanism of action and determinants of response to BCG remain obscure. We have established a model system to study the interaction of BCG with bladder cancer cells and have begun by investigating the mechanism of BCG uptake by bladder cancer cells. Surprisingly, the uptake of BCG by bladder cancer cells is through macropinocytosis rather than phagocytosis. Entry of BCG into bladder cancer cells is dependent on Rac1, Cdc42, and the downstream kinase Pak1. Additionally, we have shown that the difference in susceptibility between BCG-permissive and BCG-resistant bladder cancer cells is due to oncogenic activation of signaling pathways that activate macropinocytosis. These results demonstrate that oncogenic activation of macropinocytosis determines uptake of BCG by bladder cancer cells, and imply that tumor responsiveness to BCG may be governed by the complement of tumor promoting mutations in the treated cancer cell.

In collaboration with our clinical colleagues in urology and genitourinary oncology, we are currently expanding our studies to investigate markers of response to BCG in clinical samples and performing genetic screens investigating the host and pathogen determinants of BCG infection in bladder cells.