Philip Kranzusch, PhD, CRI Lloyd J. Old STAR Dana-Farber Cancer Institute Area of Research: All Cancers Human cells use signals called “nucleotide second messengers” to stimulate the immune response and prevent disease. These signals are produced in response to pathogen infection and cellular stress, and are important for controlling cellular communication. Recent evidence demonstrates that a nucleotide second messenger signaling enzyme named cyclic GMP–AMP synthase (cGAS) is a critical component of the immune response to many types of cancer. Drug analogues developed from these signals are rapidly emerging as promising new therapies, illustrating the importance of discovery and mechanistic understanding of naturally occurring nucleotide signals. Dr. Kranzusch has discovered that cGAS is part of a broad family of signaling enzymes. His research reveals thousands of uncharacterized cGAS-like enzymes and demonstrates that many signaling pathways remain to be discovered. Human cells respond to diverse nucleotide second messengers, and thus these results demonstrate that new nucleotide signaling pathways impact many areas of human biology and disease. Therefore, he has developed an innovative approach to uncover the function of these pathways and explain how cells use cGAS-like enzymes to control signaling. Dr. Kranzusch’s proposed research will define at the molecular level how cGAS-like enzymes are activated and enable discovery of new nucleotide signals that control antitumor immunity. Specifically, these experiments will use biochemistry and structural biology to explain the mechanism of how cGAS-like enzymes sense foreign cancer- and pathogen-derived stimuli and alert the immune system. Dr. Kranzusch has shown that human cGAS evolved from an ancient signaling pathway conserved in bacteria. As an additional innovative approach, he will leverage the emerging connection between human immunity and bacterial signaling to discover new nucleotide signals that stimulate immune responses. These experiments will define the function of cGAS-like enzymes and explain the molecular rules that allow nucleotide second messengers to control the cellular response to cancer and pathogen infection. Projects and Grants Controlling Activation of STING Responses in Cancer Immunotherapy Dana-Farber Cancer Institute | All Cancers | 2017 cGAS-like receptors and novel nucleotide signals in antitumor immunity Dana-Farber Cancer Institute | All Cancers | 2022
