Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

Abstract

Breast cancer is the most common type and one of the major causes of cancer death in woman worldwide. Epidemiological studies have established a link between night shift work and increased cancer risk, suggesting that circadian disruption may interfere with carcinogenesis. We aim to shed light on the effect of chronic jetlag on mammary tumour development. Therefore, we used a mouse model of spontaneous mammary tumorigenesis that we exposed to chronic circadian disruption. We observed that circadian disruption significantly increases cancer cell dissemination and metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. We finally showed that all these defects can be corrected by the use of a CXCR2 inhibitor. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.

Disruption of Circadian Clock Induces Abnormal Mammary Morphology and Aggressive Basal Tumorigenesis by Enhancing LILRB4 Signaling

“…LILRB4 expression was increased in mammary glands and CRD-induced mammary tumors, revealing an unidentified mechanism responsible for CRDinduced tumorigenesis, lung metastasis, and mammary gland development. The jet lag protocol used here mimics the effects of rotating shift work or frequent eastbound trans-meridian flights and has been previously shown to cause severe perturbations of circadian rhythmicity (Papagiannakopoulos, Bauer et al 2016, Hadadi, Taylor et al 2020, Pariollaud, Ibrahim et al 2022. Consistent with the results of published studies (Pariollaud, Ibrahim et al 2022), we found that CRD affected the rhythmicity of many clock genes (e.g., Clock, Bmal1, Per1, and Cry1) in the mammary glands; however, Per2 expression remained rhythmic after CRD, indicating that Per2 is more sensitive to phase entrainment signals of molecular oscillators in peripheral tissues.…”

Stromal Expression of the Core Clock Gene Period 2 Is Essential for Tumor Initiation and Metastatic Colonization

“…Disrupted circadian rhythms are generally thought to contribute to tumorigenesis and poor prognosis ( Savvidis and Koutsilieris, 2012 ; Hadadi et al, 2019 ). However, much of the work performed on cancer and rhythmicity, to date, was done in a context in which both cancer cells and their microenvironment have disrupted clocks.…”

“…The circadian clocks act as oscillators to drive 24-h rhythms in gene expression and protein function, and these rhythms help the organism maintain a homeostatic relationship with the environment ( Padmanabhan and Billaud, 2017 ). Disruption of circadian rhythms has been associated with various forms of cancer in humans, and it has been shown that a disordered circadian clock, whether genetically or due to environmental signals (e.g., changes of dark/light exposure) accelerates tumor progression ( Savvidis and Koutsilieris, 2012 ; Hadadi et al, 2019 ). Additionally, epidemiological studies show that women who work in irregular shift work may be at higher risk of developing breast cancer ( Schernhammer et al, 2003 ; Hansen and Stevens, 2012 ; Blakeman et al, 2016 ).…”

“…This is partially due to the fact that the vast majority of published studies on cancer and circadian clocks used mouse models in which both the TME and the cancer cells are affected by a disrupted clock, either by genetic mutations or by environmental cues. Recently it was shown that mice with environmentally disrupted clocks had a more protumorigenic immune microenvironment in breast cancer ( Hadadi et al, 2019 ) and thoracic cancer ( Yang et al, 2019 ). Pan-cancer analysis supported these findings, and suggested that circadian genes are involved in the regulation of cancer immunity ( Zhou et al, 2020 ).…”

A pyroptosis-related gene signature predicting survival and tumor immune microenvironment in breast cancer and validation

“…More and more studies have shown that tumor microenvironment (TME) and tumor stemness are closely related to BC occurrence and development [ 26 , 27 ], infiltration of numerous inflammatory cells in BC, and the density of CD8+ T cells is highly related to the immune escape of BC [ 28 , 29 ]. PD-1 and PD-L1 constitute an essential inhibitory mechanism which causes T cell exhaustion in tumor microenvironment.…”