| Project Detail |
Circadian rhythms (CRs) are the biological response to the periodic rotations of the Earth, and allow
fundamental adaptations of organisms to a changing environment. CRs are molecularly controlled in every cell
by a set of transcriptional factors that control, and are influenced by, core biological processes including
metabolic, immune, and proliferative.
My previous studies established, for the first time, that innate immune cells regulate the circadian physiology
of tissues, including the susceptibility of the lung to be metastasized. In INN-TIME, I ask the reciprocal
question 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 processes
rewire CRs of the host and to elucidate strategies that halt this subversion as a new approach to fight
cancer. Using lung cancer as proof-of-principle, I will first investigate cell-intrinsic circadian programs in
tumors (Aim1). Next, I will define how tumors co-opt circadian clocks of the host and explore how the
molecular clock of innate immune (Aim2) and supporting stromal cells (Aim3) impacts tumor growth, both
molecularly and functionally. By integrating multiple transcriptomics and functional approaches, INN-TIME
will discover novel regulatory programs in tumors using a circadian approach, and pave the way to design
strategies 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 of
circadian rhythms and their impact on host defense. This research will establish a new paradigm by revealing
the mechanisms underlying pro-tumorigenic clocks, and will provide robust foundations for new therapies
in a set of disorders in which circadian clock (dys)functions are implicated. |
