PIKBETA/CANCER

Role of the PI3Kbeta isoform in signalling and cancer invasion

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 Obiettivo del progetto (Objective)

'PI 3-kinases (PI3Ks) generate lipids in cell membranes which bind a variety of intracellular protein effectors, affecting their localization and/or activity. The PI3K signalling axis is one of the most frequently deregulated pathways in cancer. Mammals have 8 isoforms of PI3K, divided into three classes. The class I PI3Ks consist of a p110 catalytic subunit (p110alpha, p110beta, p110delta and p110gamma) bound to a regulatory subunit. Recent work has revealed that PI3K isoforms have surprisingly distinct roles in biology. Compared to the other class I PI3Ks, the organismal role and signalling of p110beta is poorly understood. My preliminary data point to a new and unexpected role of p110beta isoform in the control of breast cancer invasion and endosomal functions. My hypothesis is that these two phenomena are interconnected. In this proposal, I seek to investigate the role and mechanism of action of p110beta in breast cancer cell invasion. I will determine effectors downstream of p110beta involved in the control of cancer cell shape, motility and invasion and unravel molecular details of how p110beta transmits signals in the cell, with a focus on endosomal biology in the context on cell invasion. This will be achieved combining both cell-based in vitro 3D-invasion techniques using p110beta-selective pharmacological inhibitors and in vivo models of cancer invasion using mice expressing an inactive p110beta. An siRNA screen as well and advanced techniques of microscopy, biochemistry and cell biology will be performed. The results of these studies have implications for the fundamental understanding of PI3K function and the use of PI3K isoform-selective inhibitors in cancer.'

Introduzione (Teaser)

PI3-kinases (PI3Ks) modify cell membrane lipids that bind a variety of intracellular proteins and affect their localisation and activity. PI3Ks signalling is one of the most frequently deregulated pathways in cancer.

Descrizione progetto (Article)

Recently, it was demonstrated that PI3K isoforms have very distinct roles in biology. The p110beta isoform of PI3K is poorly understood but preliminary data indicates some role in controlling breast cancer invasion and endosomal functions. Endosomal functions are required for intra- and extra-cellular trafficking of molecules.

The objective of the EU-funded 'Role of the PI3Kbeta isoform in signalling and cancer invasion' (PIKBETA/CANCER) proposal was to decipher a mechanism of action of p110beta in breast cancer cell invasion and metastasis. Project members also investigated how p110beta transmits signals to downstream effectors during intracellular trafficking.

Researchers discovered that p110beta acts as a suppressor of breast cancer invasion in vitro. Using in vitro invasion assays, they demonstrated that inhibition of p110beta by selective inhibitors enhances murine and human breast cancer cell invasion. Inhibition of other PI3K isoforms such as p110 alpha or p110delta did not have the same biological effect. Moreover, pre-treating murine breast cancer cells with p110beta-selective inhibitors increased lung metastasis in mice.

In vivo experiments proved further that p110beta activity suppresses breast cancer metastasis. Researchers injected human breast cancer cells into immune-suppressed mice and then treated them with p110beta pharmacological inhibitor for several days. The results clearly showed that upon p110beta inhibition, more metastasis was observed both in the liver and lungs.

It is well known that endosomal trafficking of receptors is highly important for proliferation and migration of cancer cells. Researchers found that under p110beta inhibition, rab5 positive endosomes were abnormally enlarged suggesting a delay in endosomal trafficking.

The project results are very important for the fundamental understanding of PI3Ks function and the use of PI3K inhibitors in cancer. The work has clinical implications as several companies are currently studying class I PI3K inhibitors for application in oncology.