Grant: Project Grant

Cancer cells can be recognized by several changes they exhibit compared to normal cells. Some of these changes are in the abundance and function of proteins that are used by normal cells under only specific circumstances to divide and grow - these are called "signaling proteins". The alterations that cancer cells have in these signaling proteins allow them to divide and grow in an uncontrolled manner, leading to tumor progression. Obtaining a better understanding of how these signaling proteins work will reveal new ways to treat cancer. This research will focus on a specific set of signaling proteins that are altered in more than 75% of cancers, called the PI3K-Akt pathway. Proteins in this pathway transmit signals for cell growth and division like a relay - when one protein receives a signal and becomes activated, it has to contact the next protein in the pathway to trigger its activation. While the PI3K-Akt "signaling relay" is known to drive tumor progression, we still don't understand how the signals travel from one protein to the next. We discovered that the proteins in this pathway do not randomly find the next protein in the relay. Instead, signals do not operate unless the signaling proteins are all anchored in tiny structures called clathrin signalosomes near the cancer cell surface. To exploit this key vulnerability of the PI3K-Akt pathway to develop new cancer therapies, we first need to resolve how clathrin signalosome structures control this signaling pathway. To uncover how clathrin signalosomes control signal relays and tumor progression, we will use several different approaches including advanced microscopy of cells engineered to contain fluorescent versions of specific key proteins, allowing us to "see" proteins using advanced microscopes. This will reveal how clathrin signalosomes work within healthy and cancer cells to control signaling proteins, thus revealing new vulnerabilities to exploit for the development of new cancer treatments.