INN-TIME · Co-option of host circadian rhythms in cancer

Circadian rhythms (CRs) are the biological response to the periodic rotations of the Earth, and allowfundamental adaptations of organisms to a changing environment. CRs are molecularly controlled in every cellby a set of transcriptional factors that control, and are influenced by, core biological processes includingmetabolic, immune, and proliferative.My previous studies established, for the first time, that innate immune cells regulate the circadian physiologyof tissues, including the susceptibility of the lung to be metastasized. In INN-TIME, I ask the reciprocalquestion to reveal if tumors take advantage of, and subvert, CRs of the innate (immune and stroma)compartments to escape anti-tumoral defense. INN-TIME Aims to understand how oncogenic processesrewire CRs of the host and to elucidate strategies that halt this subversion as a new approach to fightcancer. Using lung cancer as proof-of-principle, I will first investigate cell-intrinsic circadian programs intumors (Aim1). Next, I will define how tumors co-opt circadian clocks of the host and explore how themolecular clock of innate immune (Aim2) and supporting stromal cells (Aim3) impacts tumor growth, bothmolecularly and functionally. By integrating multiple transcriptomics and functional approaches, INN-TIMEwill discover novel regulatory programs in tumors using a circadian approach, and pave the way to designstrategies to prevent cancer by interfering with tumor-supportive circadian programs.INN-TIME will revolutionize the way we understand cancer, as it will identify the malignant roots ofcircadian rhythms and their impact on host defense. This research will establish a new paradigm by revealingthe mechanisms underlying pro-tumorigenic clocks, and will provide robust foundations for new therapiesin a set of disorders in which circadian clock (dys)functions are implicated.