Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-beta-myoCAF-Dependent Mechanism

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grant; NOVO Nordisk Foundation; Knut and Alice Wallenbergs Foundation; Robert Lundberg Memorial Foundation [2021-00668]; National Key R & D Program of China [2020YFC0846600]; Volkswagen Stiftung