MICA: The network of class I PI3K interacting proteins is dramatically rewired in a PTEN-/- mouse model of prostate cancer. What are the implications?

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Cancer is a disease caused by accumulation of mutations that change the cancer cells in ways that allow them to avoid the normal restraints on their growth, survival and proliferation. Despite this simple truth understanding how mutations give cancer cells an advantage can be difficult to address yet is critical to creating strategies to kill cancer cells selectively. The major problems arise from the fact there are many changes in cancer cells that are merely reactions to the key driving events and actually make no difference to cancer progression. This project aims to understand how loss of a gene that normally resists cancer (PTEN) and is very commonly a key causal event in prostate cancer gives cancer cells an advantage. We have assembled a large amount of unpublished data using a combination of new genetic strategies to dissect signalling inside normal and cancerous mouse prostate cells. This work has revealed a totally unappreciated mechanism by which loss of PTEN can give prostate (or potentially other cell types in which PTEN is lost) new properties that help them avoid normal restraints on their growth, survival and proliferation. The mechanisms work like an in-built growth accelerator that partially bypasses the need for the driver to push on the gas pedal. We propose to do this work using a mouse model of cancer, and cultured cells derived from them, where it is possible to make single mutations and study their impacts in isolation from many other mutations and changes that have accumulated in human cancers. We will test if genetically removing the molecules that constitute the in-built accelerator mechanism slows cancer progression. Through this strategy we can build a detailed understanding of the key events causing or enabling cancer progression and hence focus efforts into creating new therapeutics into right places.