Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction

Background:Tumor metastasis is a major threat to cancer patient survival.The organ-specific niche plays a pivotal role in tumor organotropic metas-tasis.Fibroblasts serve as a vital component of the metastatic microenviron-ment,but how heterogeneous metastasis-associated fibroblasts(MAFs)promote organotropic metastasis is poorly characterized.Here,we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.Methods:Mouse models of breast cancer pulmonary metastasis were estab-lished using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung.Single-cell RNA-sequencing(scRNA-seq)was employed to investigate the heterogeneity of MAFs.Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts(TDO2^(+)MFs)in lung metastasis.Results:We uncovered 3 subtypes of MAFs in the lung metastatic microenviron-ment,and their transcriptome profiles changed dynamically as lung metastasis evolved.As the predominant subtype,MFs were exclusively marked by platelet-derived growth factor receptor alpha(PDGFRA)and mainly located on the edge of the metastasis,and T cells were enriched around MFs.Notably,high MF sig-natures were significantly associated with poor survival in breast cancer patients.Lung metastases were markedly diminished,and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse mod-els.We found that TDO2^(+)MFs controlled pulmonary metastasis by producing kynurenine(KYN),which upregulated ferritin heavy chain 1(FTH1)level in dis-seminated tumor cells(DTCs),enabling DTCs to resist ferroptosis.Moreover,TDO2^(+)MF-secreted chemokines C-C motif chemokine ligand 8(CCL8)and C-C motif chemokine ligand 11(CCL11)recruited T cells.TDO2^(+)MF-derived KYN induced T cell dysfunction.Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.Conclusions:Our study reveals crucial roles of TDO2^(+)MFs in promoting lung metastasis and DTCs’immune evasion in the metastatic niche.It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF–TrkB Signaling

Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors(SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress(6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However,combined treatment with fluoxetine and melatonin at theselected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor(BDNF)–tropomyosin receptor kinase B(Trk B) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF–Trk B signaling.

Increased mitochondrial fission drives the reprogramming of fatty acid metabolism in hepatocellular carcinoma cells through suppression of Sirtuin 1

Background:Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes.Recently,abnormally increased mitochondrial fission has been observed in several types of can-cer.However,the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear.This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepa-tocellular carcinoma(HCC)cells.Methods:Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content.The rate of fatty acid oxidation was evaluated by[PH]-labelled oleic acid.The mito-chondrial morphology in HCC cells was evaluated by fluorescent staining.The expression of protein was determined by real-time PCR,imnmunohistochemistry and Western blotting.Results:Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase(FASN),acetyl-CoA carboxylasel(ACCI),and elonga-tion of very long chain fatty acid protein 6(ELOVL6),while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A(CPTIA)and acyl-CoA oxidase 1(ACOX1).Consistently,suppressed mitochondrial fission exhibited the opposite effects.Moreover,in vitro and in vivo studies revealed that mitochondrial fission-induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells.Mechanistically,mito-chondrial fission increased the acetylation level of sterol regulatory element-binding protein 1(SREBPI)and peroxisome proliferator-activated receptor coaC-tivator 1 alpha(PGC-1a)by suppressing nicotinamide adenine dinucleotide(NAD+)/Sirtuin 1(SIRTI)signaling.The elevated SREBP1 then upregulated the expression of FASN,ACC1 and ELOVL6 in HCC cells,while PGC-1c/PPARa sup-pressed the expression of CPTIA and ACOXL Conclusions:Increased mitochondrial fission plays a crucial role in the repro-gramming of lipid metabolism in HCC cells,which provides strong evidence for the use of this process as a drug target in the treatment of this malignancy.

Correlations Between Single Nucleotide Polymorphisms,Cognitive Dysfunction,and Postmortem Brain Pathology in Alzheimer's Disease Among Han Chinese

In this study, the distribution of five Alzheimer's disease(AD)-related single nucleotide polymorphisms(SNPs) in the Han population was examined in combination with the evaluation of clinical cognition and brain pathological analysis. The associations among SNPs,clinical daily cognitive states, and postmortem neuropathological changes were analyzed in 110 human brains from the Chinese Academy of Medical Sciences/Peking Union Medical College(CAMS/PUMC) Human Brain Bank.APOE ?4(OR = 4.482, P = 0.004), the RS2305421 GG genotype(adjusted OR = 4.397, P = 0.015), and the RS10498633 GT genotype(adjusted OR = 2.375,P = 0.028) were associated with a higher score on the ABC(Ab plaque score, Braak NFT stage, and CERAD neuritic plaque score) dementia scale. These results advance our understanding of the pathogenesis of AD,the relationship between pathological diagnosis and clinical diagnosis, and the SNPs in the Han population for future research.

Increased mtDNA copy number promotes cancer progression by enhancing mitochondrial oxidative phosphorylation in microsatellite-stable colorectal cancer

Colorectal cancer is one of the leading causes of cancer death worldwide.According to global genomic status,colorectal cancer can be classified into two main types:microsatellite-stable and microsatellite-instable tumors.Moreover,the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms.Recently,mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal cancer.However,the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer,which accounts for the majority of colorectal cancer,remain unclear.In this study,we systematically investigated the functional role of altered mitochondrial DNA copy number in the survival and metastasis of microsatellite-stable colorectal cancer cells.Moreover,the underlying molecular mechanisms were also explored.Our results demonstrated that increased mitochondrial DNA copy number by forced mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellitestable colorectal cancer cells both in vitro and in vivo.Moreover,we demonstrated that increased mitochondrial DNA copy number enhanced the metastasis of microsatellite-stable colorectal cancer cells.Mechanistically,the survival advantage conferred by increased mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative phosphorylation.Furthermore,treatment with oligomycin significantly suppressed the survival and metastasis of microsatellite-stable colorectal cancer cells with increased mitochondrial DNA copy number.Our study provides evidence supporting a possible tumor-promoting role for mitochondrial DNA and uncovers the underlying mechanism,which suggests a potential novel therapeutic target for microsatellite-stable colorectal cancer.

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Mitochondrial calcium uniporter(MCU)has an important role in regulating mitochondrial calcium(Ca^(2+))homeostasis.Dysregulation of mitochondrial Ca^(2+)homeostasis has been implicated in various cancers.However,it remains unclear whether MCU regulates mitochondrial Ca^(2+)uptake to promote cell growth in colorectal cancer(CRC).Therefore,in the present study the expression of MCU in CRC tissues and its clinical significance were examined.Following which,the biological function of MCUmediated mitochondrial Ca^(2+)uptake in CRC cell growth and the underlying mechanisms were systematically evaluated using in in vitro and in vivo assays,which included western blotting,cell viability and apoptosis assays,as well as xenograft nude mice models.Our results demonstrated that MCU was markedly upregulated in CRC tissues at both the mRNA and protein levels.Upregulated MCU was associated with poor prognosis in patients with CRC.Our data reported that upregulation of MCU enhanced the mitochondrial Ca^(2+)uptake to promote mitochondrial biogenesis,which in turn facilitated CRC cell growth in vitro and in vivo.In terms of the underlying mechanism,it was identified that MCU-mediated mitochondrial Ca^(2+)uptake inhibited the phosphorylation of transcription factor A,mitochondrial(TFAM),and thus enhanced its stability to promote mitochondrial biogenesis.Furthermore,our data indicated that increased mitochondrial Ca^(2+)uptake led to increased mitochondrial production of ROS via the upregulation of mitochondrial biogenesis,which subsequently activated NF-κB signaling to accelerate CRC growth.In conclusion,the results indicated that MCU-induced mitochondrial Ca^(2+)uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM,thus contributing to CRC cell growth.Our findings reveal a novel mechanism underlying mitochondrial Ca^(2+)-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.