Glutamine metabolic microenvironment drives M2 macrophage polarization tomediate trastuzumab resistance in HER2-positive gastric cancer

Background:Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2(HER2)-positive gastric cancer.However,the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit,and there is currently no effective reversal measure.Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves,while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking.This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.Methods:Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing.Bioinformatics were used to analyze cell subtypes,metabolic pathways,and molecular signaling pathways.Changes in microenvironmental indicators(such as macrophage,angiogenesis,and metabolism)were verified by immunofluorescence(IF)and immunohistochemical(IHC)analyses.Finally,a multi-scale agent-based model(ABM)was constructed.The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.Results:Based on transcriptome sequencing,molecular biology,and in vivo experiments,we found that the level of glutamine metabolism in trastuzumabresistant HER2-positive cells was increased,and glutaminase 1(GLS1)was significantly overexpressed.Meanwhile,tumor-derived GLS1 microvesicles drove M2macrophage polarization.Furthermore,angiogenesis promoted trastuzumab resistance.IHC showed high glutamine metabolism,M2 macrophage polarization,and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nudemice.Mechanistically,the cell division cycle 42(CDC42)promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B(NF-κB)p65 and drove GLS1microvesicle secretion through IQmotif-containing GTPase-activating protein 1(IQGAP1).Based on the ABM and in vivo experiments,we confirmed that the combination of anti-glutamine metabolism,anti-angiogenesis,and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.Conclusions:This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism,M2 macrophage polarization,and pro-angiogenic function of macrophages,leading to acquired trastuzumab resistance in HER2-positive gastric cancer.A combination of anti-glutamine metabolism,anti-angiogenesis,and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.

Quasi-3-yr Cycle of Rainy Season Precipitation in Tibet Related to Different Types of ENSO during 1981–2015

The rainy season precipitation in Tibet（RSPT） is a direct cause for local floods/droughts. It also indirectly affects the thermal conditions of the Tibetan Plateau, which can result in anomalous patterns of atmospheric circulation over East Asia. The interannual variability of the RSPT is often linked with the El Ni？o–Southern Oscillation（ENSO）, but the relevant mechanisms are far from being understood, particularly for different types of ENSO events. We investigated the interannual variation of the RSPT in association with different types of ENSO. A quasi-3-yr period of the RSPT（less–more–more precipitation） was significant at the 95% confidence level. A joint multi-taper method with singular value decomposition analysis of the coupled field between the RSPT and the sea surface temperature（SST）revealed that the developing eastern Pacific type El Ni？o was accompanied by a decrease in the RSPT. The shift from the central Pacific type El Ni？o to the eastern Pacific La Ni？a was accompanied by an increase in the RSPT. Weakening of the central Pacific La Ni？a was accompanied by an increase in the RSPT. Analysis of the mechanism of this coupling, using the same analysis method but other climatic factors, indicated that the gradually strengthening eastern Pacific El Ni？o can inhibit the Walker circulation, weakening the South Asian summer monsoon, and resulting in transport of less water vapor from the Bay of Bengal to Tibet. The change from the central Pacific El Ni？o to the eastern Pacific La Ni？a led to continued strengthening of the Walker circulation with westward movement of the ascending area. This enhanced the South Asian summer monsoon over the Arabian Sea and transported more water vapor to Tibet. The decreasing central Pacific La Ni？a accompanied by persistent cooling of SSTs in the equatorial Pacific led to a strong eastern North Pacific summer monsoon, causing an anomaly in the easterly transport of water vapor from the Sea of Japan to Tibet and increased RSPT.