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

Abstract

The circadian clock regulates diverse physiological processes by maintaining a 24-h gene expression pattern. Genetic and environmental cues that disrupt normal clock rhythms can lead to cancer, yet the extent to which this effect is controlled by the cancer cells versus non-malignant cells in the tumor microenvironment (TME) is not clear. Here we set out to address this question, by selective manipulation of circadian clock genes in the TME. In two different mouse models of cancer we find that expression of the core clock gene Per2 in the TME is crucial for tumor initiation and metastatic colonization, whereas another core gene, Per1 , is dispensable. We further show that loss of Per2 in the TME leads to significant transcriptional changes in response to cancer cell introduction. These changes may contribute to a tumor-suppressive microenvironment. Thus, our work unravels an unexpected protumorigenic role for the core clock gene Per2 in the TME, with potential implications for therapeutic dosing strategies and treatment regimens.

Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment

“…Similarly, by multi-omics computation techniques, several core circadian clock genes are found changed epigenetically in lung adenocarcinomas and lung squamous cell carcinomas, which are involved in cell cycle and apoptosis, such as PER2 and RORA ( Yang et al, 2019 ). By applying MC38, a colorectal cancer cell line, in a syngeneic mouse model of liver metastasis, Per1 –/– Per2 –/– mice had reduced liver metastasis, and Per2 –/– livers had less cancer-associated fibroblasts infiltration and collagen deposition ( Shaashua et al, 2020 ). Further characterizations revealed that stromal Per2 is also required for primary tumor formation ( Shaashua et al, 2020 ).…”

“…By applying MC38, a colorectal cancer cell line, in a syngeneic mouse model of liver metastasis, Per1 –/– Per2 –/– mice had reduced liver metastasis, and Per2 –/– livers had less cancer-associated fibroblasts infiltration and collagen deposition ( Shaashua et al, 2020 ). Further characterizations revealed that stromal Per2 is also required for primary tumor formation ( Shaashua et al, 2020 ). This finding implies the importance of PER family genes in TME.…”

Period 2 Suppresses the Malignant Cellular Behaviors of Colorectal Cancer Through the Epithelial-Mesenchymal Transformation Process

“… 33 Recently, it has been found that an imbalance in PER2 gene expression is associated with NSCLC, 12 ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, thyroid cancer, and so on. 16 , 33 - 35 However, it has been reported that PER2 not only has anti-cancer effects in CRC but also has carcinogenic effects, 18 , 19 indicating that the expression of PER2 is controversial. The most important thing regarding PER2 is that the latest research shows that it is associated with the tumorigenesis and development of gastric cancer.…”

“… 12 , 13 , 15 - 18 Meantime, it is also discovered that PER2 in TME has unexpected tumorigenic effects in the liver metastasis model of colon cancer in mice. 19 So the expression of PER2 in CRC is controversial. Therefore, it is necessary to clarify the role of PER2 in CRC and the specific underlying molecular mechanism.…”

Current Trends and Research Topics Regarding Intestinal Organoids: An Overview Based on Bibliometrics

“…Sixty percent of all CRC cases arise from adenomatous polyps following the adenoma-carcinoma sequence (also named the conventional pathway) ( Lau et al, 2020 ; Shaashua et al, 2020 ). Wnt signaling is continuously activated in the intestinal organs of APC-deficient mice, which interferes with the differentiation process.…”