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Good or bad calcium, who decides?

Calcium signals trigger T cells to destroy pathogens, but frustratingly, they also spur cancer cell metastasis. The difference lies in the way calcium signals are adjusted and redirected. The initial signal hinges on ORAI, a protein that channels calcium into the cell, and the consequences depend on the proteins that network with ORAI.

Some of these proteins will adjust the level of calcium coming into the cell. In contrast, others will be huddled around ORAI, waiting to be activated by the calcium ions that gush in through the ORAI channel. Akin to a relay race, these proteins will go on to perform their unique functions in the cell. Depending on who gets involved, the outcomes can be good or bad. For instance, immune cells revamp their calcium signals and become more mobile, to target and destroy damaged or pathogenic cells. Cancer cells, on the other hand, hijack calcium signals, and they too become more mobile, but only to provoke uncontrolled cell growth and metastasis.

The proteins that network with ORAI are largely unidentified. I designed a way to tag exclusively the proteins closest to ORAI when calcium flow is on. A challenging series of experiments led to the identification of around 200 candidate proteins that belong to the ORAI signaling hub.

SPARK funding will enable me to determine which of these proteins have a measurable impact on calcium signaling, and therefore, should be prioritized for detailed future investigations. With the top candidates, I will test how they shape calcium signals, in two kinds of experiments. First, I will test whether they talk to ORAI to directly increase or decrease calcium signals. Or whether they listen to ORAI and relay a signal that alters the cell’s structural framework or mobility, two critical functions driven by calcium signals.

Derailed calcium signaling is an important but less explored clinical target in cancer therapy. ORAI is present in all healthy and cancer cells, but proteins partnering with ORAI in different cells to drive specific and distant outcomes are preferred targets that can potentially be translated into therapeutic agents