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

Abstract

Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.

Metastasis of Breast Cancer Promoted by Circadian Rhythm Disruption due to Light/Dark Shift and its Prevention by Dietary Quercetin in Mice

“…But it did not affect the tumor volume or weight of transplanted breast tumors ( Figure 2C and 2D ). The effect of biorhythm disturbance on tumor growth and metastasis has been reported in previous study [ 42 ], along with downregulation of per2 by jet lag condition. And, it presents interesting data on the acquisition of the stemness and growth potential of tumor cells and antitumor immunity.…”

“…In contrast, as mentioned above, our model did not show the effect of light-disturbance on tumor growth. It is difficult to make a general comparison with previous study [ 42 ], because of the different tumor model (spontaneous or orthotopic transplant), subtypes of breast cancer cells (estrogen receptor and progesterone receptor sensitivity and HER2 protein expression) and light/dark conditions. Therefore, we think that it will be necessary to consider the systems that more closely resemble human rotating shift work, e.g., comparison with a 3-shift work system (shifted by 8 hours for 3 groups), of different light-dark compositions (6:18 light:dark cycle, and/or 18:6 light:dark cycle) in future studies.…”

Do malignant cells sleep at night?

“…These two axes recruit myeloid-derived suppressor cells into the tumor micro-environment, promoting cancer cell dissemination and metastasis formation. In agreement, inhibition of the CXCL5-CXCR2 axis limits the number of metastasis in mice [124]. The higher expression of components of these two axes upon circadian disruption might increase CTC fitness.…”

Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation

“…In rats carrying tumors, NK cells from the spleen showed higher nocturnal levels of granzyme B, perforin, and interferon-γ, which were lost under a CJL schedule ( 6 ). Similarly, changes in the immune microenvironment inside the tumor, particularly in macrophage and T helper lymphocyte profiles, have been recently reported in a different murine model of tumorigenesis subject to circadian deregulation ( 29 ). Together, these data suggest a strong effect of circadian desynchronization on the immune system.…”