Co-option of host circadian rhythms in cancer

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.