Cancer Discovery . . . Dr. Chen Peiwen and others reveal the molecular mechanisms of double regulation of glioma stem cells and tumor immunity.

Glioblastoma (GBM) is one of the most common brain tumors with a high mortality rate. At present, there is almost no effective treatment.the average survival time of patients diagnosed is only 12 to 15 months, and less than 5% of them can survive for 5 years.drug resistance, tumor heterogeneity and tumor immune cell infiltration are the three important characteristics of GBM.glioma stem cells (GSCs) are one of the key cells leading to drug resistance and tumor heterogeneity. Tumor associated macrophages / microglia (TAMs) are the most common immune cells in GBM (macrophages and microglia account for 85% and 15% respectively).therefore, to study the mechanism of GSCs and TAMs on the occurrence and progression of GBM is expected to identify new therapeutic targets.in 2019, Dr. Chen Peiwen published an article in cancer cell, reporting that lysine oxidase (LOX) is a new macrophage chemokine, and reveals its molecular mechanism of regulating macrophage infiltration and promoting tumor progression. However, the molecular mechanism of microglia infiltration in GBM is still unclear.the occurrence of GBM is related to the genetic mutation of three signaling pathways (RTK / Ras / PI3K / PTEN, p53 / ARF / MDM2 and Rb / CDKN2A).however, due to the genetic instability and heterogeneity of tumors, the treatment of these signaling pathways has failed in clinical trials.in recent years, more and more studies have shown that epigenetic disorders play an important role in tumorigenesis.these epigenetic factors can regulate the formation of the main characteristics of GBM, such as GSC dryness and tumor immunity. Therefore, we have identified epigenetic factors that play a dual role in regulating GSCs dryness and tumor immunity, which is expected to develop more effective therapeutic strategies for GBM.on January 9, 2020, Professor Ronald a. depinho (former president of MD Anderson Cancer Center) of University of Texas (Dr. Chen Peiwen as the first author of the article) published an article "circular Regulator Clock recurrences immune suppressive microglia into the GBM tumor" in cancer discovery We successfully identified the dual roles of clock related protein clock in regulating GSCs dryness and tumor immunity, and revealed its mechanism and potential value as a target for GBM therapy.through epigenetic screening, the author identified that clock related protein has the strongest ability to promote the self-proliferation of neural stem cells. It is worth mentioning that clock is a potential proto oncogene in GBM patients.functional experiments in vivo and in vitro showed that knockout or inhibition of clock in GSCs could significantly inhibit the self increment of GSCs by reducing glucose metabolism and fatty acid metabolism.on the other hand, we found that clock is closely related to tumor immunity through microarray selection and signal pathway analysis.further studies showed that high expression of clock could promote microglia infiltration in GBM patients, but had little effect on macrophages.mechanism studies have shown that clock, a transcription factor, can directly promote the gene expression of chemokines, and the most important one is olfml3.functional studies have shown that olfml3 is a new chemotactic factor of microglia, which can greatly promote the infiltration of microglia into GBM.in GBM mouse model and human tumor xenotransplantation model (PDX), inhibiting the function of clock and olfml3 can significantly prolong the survival time of tumor bearing mice by inhibiting the infiltration of microglia and the dryness of GSCs.in conclusion, this study identified the dual role of clock related protein clock in maintaining GSC dryness and regulating tumor immunity through epigenetic screening, and analyzed its mechanism of action, providing a dual target for GBM treatment.Dr. Peiwen Chen (Chen Peiwen), Professor Ronald a. depinho's research group, is the first author of this paper.professor depinho and Dr. y. Alan Wang are co authors of this paper.original link