Loss of cell and tissue polarity is a hallmark of epithelial cancers suggesting a crucial role for polarity regulators in suppressing tumorigenesis (1). Recent findings from the Humbert laboratory have shown that the core polarity protein Scribble is deregulated and mislocalized in human prostate cancer, which correlates with poor patient outcome in the clinic. These data indicate that furthering our understanding of how deregulation of the polarity network facilitates prostate cancer progression may prove to hold prognostic value in the clinic, as well as identify novel routes of therapeutic intervention.
Functionally, our lab has shown that Scribble deficiency in prostate epithelium is a weak initiator of prostate neoplasia in mice owing to elevated Ras/MAPK signalling (2). Furthermore, Scribble depletion promotes K-Ras-induced prostate tumorigenesis, indicating that Scribble loss can contribute to tumor progression in the presence of an additional oncogenic mutation, however no metastasis was observed (2).
To directly assess whether the polarity regulator plays a metastasis suppressive role in prostate cancer, we shall combine in vitro functional assessment of human epithelial cell lines expressing constructs to knockdown (shRNA), over-express (hSCRIB) or mislocalise (ScribP305L) Scribble together with in vivo experimental models of metastasis. In addition, we have employed a well characterised Pten deficient-induced prostate cancer transgenic mouse model (PBCre+;Ptenfl/fl) to determine whether Scribble loss can facilitate metastatic progression in this setting. Indeed, it has recently been shown that oncogenic K-Ras(G12D) in combination with Pten loss cause lymph node metastasis, demonstrating Pten loss and elevated Ras/MAPK signalling cooperate to drive metastatic progression in this model (3).
Together, this work will provide key insights into how signalling cascades mediated by core polarity proteins act to suppress tumor growth and metastasis, and may therefore assist with the development of innovative prognostic factors and development of novel therapeutic approaches involving the cell polarity network.