Co-option of host circadian rhythms in cancer

Introduction

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 functions.

Previous Studies

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.

Research Objectives

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.

Methodology

Using lung cancer as proof-of-principle, I will:

1. Investigate cell-intrinsic circadian programs in tumors (Aim 1).
2. Define how tumors co-opt circadian clocks of the host (Aim 2).
3. Explore how the molecular clock of innate immune and supporting stromal cells (Aim 3) 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.

Impact

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.