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RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

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Military Medical Research 2024年第1期11卷 34-49页

作者： Yi-Qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma Department of Medical oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

关键词： RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer

Microbiota in colorectal cancer related to liver metastasis

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Chinese Journal of Cancer Research 2024年第1期36卷 17-24页

作者： Peijun Wei Weiming Han Zitong Zhang Xue Tian Chen Yang Qiaoxuan Wang Weihao Xie Ying Liu Yuanhong Gao Hui Chang Department of Radiation oncology State Key Laboratory of Oncology in South ChinaGuangzhou 510060China Guangdong Provincial clinical Research center for Cancer Guangzhou 510060China Sun Yat-sen University Cancer center Guangzhou 510060China Department of Pediatric oncology State Key Laboratory of Oncology in South ChinaGuangzhou 510060China

The prevalence of colorectal cancer(CRC) is increasing annually and metastasis is the principal cause of death in patients with CRC, with the liver being the most frequently affected site. Many studies have shown a strong interplay between the gut flora, particularly Fusobacterium nucleatum(F. nucleatum), Escherichia coli, and Bacteroides fragilis, and the development of gut tumors. Some strains can induce gut inflammation and produce toxins that directly harm gut epithelial cells, ultimately accelerating the onset and progression of CRC. However,little clinical evidence exists on the specific interplay between the gut microflora and colorectal cancer liver metastasis(CRLM). Some research showed the existence of viable F. nucleatum in distant metastasis of CRC.Subsequently, gut microbiota products, such as lipopolysaccharides, sodium butyrate, and protein cathepsin K, were also found to affect the development of CRC. This article summarizes the mechanism and research status of the interplay between gut microflora and CRLM, discusses the importance of gut microflora in the treatment of CRLM, and proposes a new approach to understanding the mechanism of CRLM and potential treatments for the microbiome. It is anticipated that the gut microbiota will be a formidable therapeutic and prophylactic tool for treating and preventing CRLM.

关键词： Gut microbiota liver metastasis colorectal cancer

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac:Estimated delivered dose and early toxicity results

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Chronic Diseases and Translational Medicine 2024年第1期10卷 51-61页

作者： Linrui Gao Ran Wei Shirui Qin Yuan Tian Wenlong Xia Yongwen Song Shulian Wang Hui Fang Yu Tang Hao Jing Yueping Liu Yuan Tang Shunan Qi Bo Chen Yexiong Li Nianzeng Xing Ningning Lu Department of Radiation oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina GCP center/clinical Research center National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Urology State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Background: Magnetic resonance(MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation(UHF-WPRT)is a novel approach to radiotherapy for patients with high-risk(HR)and very high-risk(VHR)prostate cancer(PCa).However,the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time.We aimed to estimate the delivered dose,study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac.Methods: Ten patients with clinical stage T3a-4N0-1M0-1c PCa,who consecutively received UHF-WPRT,were enrolled prospectively.The contours of the target and organ-at-risks on the position verification-MR(PV-MR),beam-on 3D-MR(Bn-MR),and post-MR(after radiotherapy delivery)were derived from the pre-MR data by deformable image registration.The physician then manually adjusted them,and dose recalculation was performed accordingly.GraphPad Prism 9(GraphPad Prism Software Inc.)was utilized for conducting statistical analyses.Results: In total,we collected 188 MR scans(50 pre-MR,50 PV-MR,44 Bn-MR,and 44 post-MR scans).With median 59 min,the mean prostate clinical target volume(CTV)-V_(100%)was 98.59%±2.74%,and the mean pelvic CTVp-V_(100%)relative percentages of all scans was 99.60%±1.18%.The median V29 Gy change in the rectal wall was−2%(−18%to 20%).With a median follow-up of 9 months,no patient had acute Common Terminology Criteria for Adverse Events(CTCAE)grade 2 or more severe genitourinary(GU)or gastrointestinal(GI)toxicities(0%).Conclusion: UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape(ATS)workflow was technically feasible for patients with HR and VHR PCa,presenting only mild GU and GI toxicities.The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis.clinical trial registration Chinese clinical Trial Registry ChiCTR2000033382.

关键词： dosimetry hypofractionation magnetic resonance imaging prostate cancer radiation dose radiotherapy

Emerging clinical relevance of microbiome in cancer:promising biomarkers and therapeutic targets

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Protein & Cell 2024年第4期15卷 239-260页

作者： Jia-Hao Dai Xi-Rong Tan Han Qiao Na Liu State Key Laboratory of oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510050China

The profound influence of microbiota in cancer initiation and progression has been under the spotlight for years,leading to numerous researches on cancer microbiome entering clinical evaluation.As promising biomarkers and therapeutic targets,the critical involvement of microbiota in cancer clinical practice has been increasingly appreciated.Here,recent progress in this field is reviewed.We describe the potential of tumor-associated microbiota as effective diagnostic and prognostic biomarkers,respectively.In addition,we highlight the relationship between microbiota and the therapeutic efficacy,toxicity,or side effects of commonly utilized treatments for cancer,including chemotherapy,radiotherapy,and immunotherapy.Given that microbial factors influence the cancer treatment outcome,we further summarize some dominating microbial interventions and discuss the hidden risks of these strategies.This review aims to provide an overview of the applications and advancements of microbes in cancer clinical relevance.

关键词： microbiome cancer diagnosis prognosis therapy

Development of antibody-drug conjugates in cancer:Overview and prospects

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Cancer Communications 2024年第1期44卷 3-22页

作者： Dan-Yun Ruan Hao-Xiang Wu Qi Meng Rui-Hua Xu Department of clinical Research Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen UniversityGuangzhouGuangdongP.R.China Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer Chinese Academy of Medical SciencesGuangzhouGuangdongP.R.China Department of Medical oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen UniversityGuangzhouGuangdongP.R.China

In recent years,remarkable breakthroughs have been reported on antibody-drug conjugates(ADCs),with 15 ADCs successfully entering the market over the past decade.This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs,demonstrating their efficacy in treating awide array of malignancies.Nonetheless,there is still an unmet clin-ical need forwider application,better efficacy,and fewer side effects of ADCs.An ADC generally comprises an antibody,a linker and a payload,and the combina-tion has profound effects on drug structure,pharmacokinetic profile and efficacy.Hence,optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects.In this review,we comprehen-sively reviewed the current development and the prospects of ADC,provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China,highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies,and also discussed the new related technologies,possibility of next-generation ADCs and the directions of clinical research.

关键词： companies breakthrough payload

Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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oncology Research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI Medical oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell death.Apatinib is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis pathway.However,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported yet.Tumor.secreted exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered.Here,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of Apatinib.In conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome Tyrosine kinase inhibitor Gastrointestinal tumors miRNA

Perioperative complication incidence and risk factors for retroperitoneal neuroblastoma in children:analysis of 571 patients

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World Journal of Pediatrics 2024年第3期20卷 250-258页

作者： Min He Jia-Bin Cai Xuan Wu Yin-Bing Tang Jin-Yan Wang Jun-Qin Mao Ji-Jun Chen Li-Feng Zhang Zhong-Hai Guan Jie-Ni Xiong Wan-Xin Peng Jin-Hu Wang Ting Tao Pediatric Cancer Research center National Clinical Research Center for Child HealthHangzhouChina Department of Surgical oncology Children's HospitalZhejiang University School of MedicineHangzhouChina Cancer center Zhejiang UniversityNo.3333 Binsheng RodeHangzhouChina

Background Surgery plays an important role in the treatment of neuroblastoma.Perioperative complications may impact the course of neuroblastoma treatment.To date,comprehensive analyses of complications and risk factors have been lacking.Methods Patients with retroperitoneal neuroblastoma undergoing tumor resection were retrospectively analyzed between 2014 and 2021.The data collected included clinical characteristics,operative details,operative complications and postopera-tive outcomes.Risk factors for perioperative complications of retroperitoneal neuroblastoma were analyzed.Results A total of 571 patients were enrolled in this study.Perioperative complications were observed in 255(44.7%)patients.Lymphatic leakage(28.4%),diarrhea(13.5%),and injury(vascular,nerve and organ;7.5%)were the most frequent compli-cations.There were three operation-related deaths(0.53%):massive hemorrhage(n=1),biliary tract perforation(n=1)and intestinal necrosis(n=1).The presence of image-defined risk factors(IDRFs)[odds ratio(OR)=2.09,P<0.01],high stage of the International Neuroblastoma Risk Group staging system(INRGSS)(OR=0.454,P=0.04),retroperitoneal lymph node metastasis(OR=2.433,P=0.026),superior mesenteric artery encasement(OR=3.346,P=0.003),and inferior mesenteric artery encasement(OR=2.218,P=0.019)were identified as independent risk factors for perioperative complications.Conclusions Despite the high incidence of perioperative complications,the associated mortality rate was quite low.Perio-perative complications of retroperitoneal neuroblastoma were associated with IDRFs,INRGSS,retroperitoneal lymph node metastasis and vascular encasement.Patients with high-risk factors should receive more serious attention during surgery but should not discourage the determination to pursue total resection of neuroblastoma.

关键词： Complication Neuroblastoma Risk factors Surgery

Pan-cancer immunogenic death analysis identifies key roles of CXCR3 and CCL18 in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 568-570页

作者： Jia Guo Xin Sun Guowei Pan Ce Li Xin He Xiaofang Che Zan Teng Xiujuan Qu Yunpeng Liu Bowen Yang Department of Medical oncology Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning ProvinceLiaoning Provincial Clinical Research Center for CancerClinical Cancer Research Center of ShenyangThe First Hospital of China Medical UniversityShenyangLiaoning 110001China Research center for Universal Health School of Public HealthChina Medical UniversityShenyangLiaoning 110122China

Immunogenic death is a form of programmed cell death that is common in the development and progression of cancer.However,its impact on tumor progression differs depending on the location of the tumor.Meanwhile,it also plays an important role in antitumor immunity because the process of immunogenic death can release substances that activate immunity.1 Therefore,in this study,the key mechanism of mediating immunogenic death in hepatocellular carcinoma(HCC)was found from the excavation of the immunogenic death characteristics of pan-cancer and the in-depth investigation of its effects on different tumor types(Fig.1A).

关键词： death CXCR3 immunity

The E3 ubiquitin ligase TRAF6 controls CTLA-4 turnover and promotes T-cell-mediated antitumor immunity

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Cellular & Molecular Immunology 2024年第1期21卷 97-99页

作者： Xiao-Liang Jie Hua Guo Guang-Biao Zhou State Key Laboratory of Molecular oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College100021 BejingChina

Yu et al.[1]reported that the tumor necrosis factor(TNF)receptor OX40(CD134)-TNF receptor-associated factor 6(TRAF6)axis mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of cytotoxic T-lymphocyte antigen 4(CTLA-4),leading to the enhancement of CD8^(+)T-cell-mediated antitumor immunity.Their findings unveil a previously unknown mechanism in controlling the stability of the immune checkpoint CTLA-4 and provide a potential therapeutic target for the improvement of Tcell-based immunotherapy.

关键词： immunity OX40 ubiquitin