NSD2

LOS ANGELES, March 14, 2024 /PRNewswire/ -- The Prostate Cancer Foundation (PCF) today announced the 2023 Class of PCF Team Challenge Award recipients and a total of more than $21 million in funding for innovative prostate cancer research. PCF Challenge Awards fund international, multi-institutional, cross-disciplinary teams of investigators conducting highly innovative research with the greatest potential for accelerating new and improved treatments for advanced prostate cancer. Following a rigorous peer review process that assessed each project's scientific merit and potential patient impact, 20 highly coveted PCF Challenge Awards totaling $21.3 million were granted to teams at some of the world's leading cancer research institutions. For full project descriptions visit . 2023 James Cox Foundation, GTSN-PCF Challenge Award Project Title: Targeting Neuroendocrine Cells in Prostate Cancer with Small Molecule and Targeted Radionuclide Therapies Principal Investigators: Andrew Armstrong, MD, and Jiaoti Huang, MD, both of Duke University (Studying the efficacy of and developing biomarkers for two new treatment approaches for neuroendocrine prostate cancer to address an unmet need encompassing precision immunotherapy for the treatment of highly aggressive forms of castration-resistant prostate cancer.) 2023 Republic National Distributing Company (RNDC)-PCF Challenge Award Project Title: Development of a CBP/p300 Degrader for the Treatment of Castration-Resistant Prostate Cancer Principal Investigators: Arul Chinnaiyan, MD, PhD; Shaomeng Wang, PhD; Ulka Vaishampayan, MBBS; Abhijit Parolia, PhD, all of University of Michigan (Developing a new therapy that targets the prostate cancer oncogenes CBP and p300, this project will provide preclinical efficacy data and analyze biomarkers of response from a phase 1/2 clinical trials in patients with metastatic castration-resistant prostate cancer.) 2023 Bayer-PCF Health Equity Research Award Project Title: Incorporating Patient Education into Germline Testing in Black Patients with Prostate Cancer Principal Investigator: Burcu Darst, PhD, Fred Hutchinson Cancer Center (With the aim of reducing prostate cancer health disparities, this project will examine whether a tailored education program increases the likelihood of Black patients to undergo genetic testing and further the understanding of how this information impacts disease management decisions.) 2023 PCF Challenge Award Project Title: Personalizing Treatment Decisions Through Composite Next Generation Imaging and Liquid Biomarker Development Within a Phase II Randomized Trial of Enzalutamide (+/- 177Lu-PSMA-617) (ENZAp) Principal Investigator: Louise Emmett, MD, MBBS, St. Vincent's Hospital, Sydney, Australia (Studying molecular imaging and liquid biopsies from patients on a clinical trial testing LuPSMA plus enzalutamide versus enzalutamide alone as first-line therapy in patients with metastatic castration-resistant prostate cancer to better understand the mechanisms of synergy and resistance and develop biomarkers to guide individualized treatment decisions for patients.) 2023 Sun Pharma-PCF VAlor Special Challenge Award Project Title: A Phase 2 Randomized Study of YONSA® (Abiraterone Acetate), Enzalutamide or Apalutamide as First Line Therapy in Veterans with Castrate-Sensitive Prostate Cancer Principal Investigators: Antonio Tito Fojo, MD, and Susan Bates, MD, both of James J. Peters Veterans Affair Medical Center (Studying the effectiveness of an abiraterone-first strategy in the management of patients with castration-sensitive prostate cancer at the time when cancer recurrence is first documented.) 2023 PCF Challenge Award Project Title: Identifying Drivers of Aggressive Prostate Cancer and Racial Disparities in Patients Presenting with Low-Grade Disease Principal Investigators: Vanessa Hayes, PhD, The University of Sydney; Gail Prins, PhD, University of Illinois at Chicago; Riana Bornman, MD, University of Pretoria (Identifying genetic and genomic risk factors of lethal prostate cancer in African ancestry patients and translating this information into new criteria for classifying, managing and treating prostate cancer in these patients in order to reduce racial health disparities.) 2023 Bayer-PCF Health Equity Research Award Project Title: Impact of Genetic Ancestry and DNA Methylation on Prostate Cancer in African and African-American Patients Principal Investigator: Brian Joyce, PhD, Northwestern University (Investigating the usefulness of DNA methylation profiling of patient samples for the early detection and risk stratification of prostate cancer in Black men.) 2023 John Black Charitable Foundation-PCF Challenge Award Project Title: Metabolic Imaging and Targeted Radionuclide Combination Treatment of Prostate Cancer Bone Metastases Principal Investigators: Edward O'Neill, PhD, Claire Edwards, PhD, both of University of Oxford (Studying the role of tumor metabolism in treatment responses to 177Lu-PSMA-617 radioligand therapy to identify potential biomarkers and therapeutic targets in advanced prostate cancer.) 2023 Bayer-PCF Health Equity Research Award Project Title: Molecular Evaluation of Prostate Saturation and Progression Biopsies for Risk Assessment and Early Intervention Principal Investigator: Nallasivam Palanisamy, PhD, MSc, Henry Ford Health System (Analyzing at the molecular level prostate tumor samples from Black and white patients to understand racial differences in prostate cancer biology and disease progression, potentially leading to improved biomarker-based risk assessment tools for Black patients to improve health outcomes and reduce disparities.) 2023 Digital Science Press-PCF Challenge Award Project Title: Intercepting the Cancer Endocycle to Cure Lethal Prostate Cancer Principal Investigators: Kenneth Pienta, MD, Johns Hopkins University; Sarah Amend, PhD, Johns Hopkins School of Medicine; Emma Hammarlund, PhD, Lund University (Investigating whether a dormant "endocycling" state underlies cancer cells' ability to survive and resist therapy and testing new therapies to target cancer cells in this state.) 2023 Bayer-PCF Darolutamide Challenge Award Project Title: Darolutamide to Augment Radiotheranostic Therapy in Biochemically Recurrent Prostate Cancer (DART-BCR) Principal Investigators: Praful Ravi, MD, Harvard: Dana-Farber Cancer Institute; David Einstein, MD, Beth Israel Deaconess Medical Center (Examining the efficacy of darolutamide alone or in combination with PSMA-targeted radioligand therapy to identify biomarkers for patients most likely to benefit from this combination therapy, and determining how PSMA, the target of prostate cancer treatments and PET imaging, is regulated.) 2023 Durden Foundation-PCF Challenge Award Project Title: Characterizing Imaging, Genomic and Immune Predictors of 177Lu-PSMA (Lu-PSMA) and Olaparib Response in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC) Principal Investigators: Shaneen Sandhu, MBBS, and Belinda Parker, PhD, both of the University of Melbourne (Testing the efficacy of a combination of Lu-PSMA and Olaparib for certain patients with mCRPC and defining the biological impacts of this combined therapy to maximize its effectiveness.) 2023 John and Daria Barry Foundation-PCF VAlor Challenge Award Project Title: Germline Influence on Prostate Cancer Metastasis and Response to Androgen Deprivation Therapy Principal Investigators: Tyler Seibert, MD, PhD, and Rana McKay, MD, of University of California San Diego; and Paul Boutros, PhD, MBA, of University of California Los Angeles (Using previously identified genetic variants that increase prostate cancer aggressiveness to develop a new genetic test that can predict individuals at high risk for developing lethal prostate cancer and their response to treatment.) 2023 Hamptons Coalition-PCF Challenge Award Project Title: Targeting Gut Bacterial Androgen Production to Reverse Therapeutic Resistance in Metastatic Prostate Cancer Principal Investigators: Karen Sfanos, PhD, Johns Hopkins University; Cathy Marshall, MD, MPH, Mark Markowski, MD, PhD, both of Johns Hopkins Medicine; Jason Ridlon, PhD, University of Illinois Urbana-Champaign (Developing and testing therapeutic strategies to prevent androgen production by gut bacteria in order to prolong the clinical response to anti-androgen therapies.) 2023 Regeneron-PCF Special Challenge Award Project Title: A Pilot Presurgical Trial of REGN5678 (Anti-PSMAxCD28) in Patients with High-Risk, Localized Prostate Cancer Followed by Radical Prostatectomy Principal Investigators: Padmanee Sharma, MD, PhD, Sumit Subudhi, MD, PhD, Brian Chapin, MD, Bilal Siddiqui, MD, all of The University of Texas MD Anderson Cancer Center (Investigating the efficacy of a new immunotherapy treatment, anti-PSMAxCD28 (REGN5678), that enables T cells to directly bind with and kill prostate cancer cells.) 2023 PCF Challenge Award Project Title: Modulation of Anti-Androgen Response by NSD2 in Castration-Resistant Prostate Cancer Principal Investigators: Michael Shen, PhD, Andrea Califano, PhD, of Columbia University Medical Center; Johann de Bono, MD, PhD, The Institute of Cancer Research; Charles L. Sawyers, MD, Memorial Sloane Kettering Cancer Center (Elucidating the mechanisms of NSD2 action, a critical driver and promising therapeutic target against highly aggressive neuroendocrine prostate cancer, to provide a foundation for early-phase trials of NSD2 inhibitors.) 2023 Bayer-PCF Darolutamide Challenge Award Project Title: Darostep: Evaluating Step Counts as a Biomarker and its Relationship on Treatment Outcomes in Vulnerable Patients with Metastatic Hormone-Sensitive Prostate Cancer on Darolutamide and Androgen Deprivation Therapy Principal Investigators: Russell Szmulewitz, MD, Nabiel Mir, MBBS, Megan Huisingh-Scheetz, all of The University of Chicago (Evaluating the impact of treatment with darolutamide on age-related outcomes in vulnerable, older patients with metastatic hormone-sensitive prostate cancer.) 2023 Movember, Todd Boehly, Shmuel Meitar, Richard Merkin, MD, Marcel Claure-PCF Challenge Award Project Title: Identification of Patients at High-Risk of Metastatic Disease After Neoadjuvant Intensive Androgen Signaling Inhibition Principal Investigators: Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute; Steven Balk, MD, PhD, Beth Israel Deaconess Medical Center (Developing biomarkers for identifying patients with high-risk localized prostate cancer who are likely to benefit from neoadjuvant androgen receptor signaling inhibitors (ARSI) which could lead to a new treatment paradigm that will cure more patients at the localized disease stage.) 2023 Igor Tulchinsky-PCF Challenge Award Project Title: ctDNA Determinants of Resistance to 177Lu-PSMA-617 versus Taxane-Based Chemotherapy Principal Investigators: Alexander Wyatt, PhD, Vancouver Prostate Centre; Arun Azad, MD, Michael Hofman, Peter MacCallum Cancer Centre; Kim Chi, MD, BC Cancer (Developing new blood-based biomarker tests to predict how well patients with metastatic castration-resistant prostate cancer will respond to 177Lu-PSMA-617 versus taxane chemotherapy while identifying new molecular mechanisms that drive treatment resistance.) 2023 Richard Solomon, Igor Tulchinsky, Darius Bikoff, John Paulson, Richard Sandler, Bill Mack, Jason Safriet-PCF Challenge Award Project Title: New Targeted Epigenetic Therapy for Androgen Receptor-Negative Prostate Cancer Principal Investigators: Ming-Ming Zhou, PhD, Icahn School of Medicine at Mount Sinai; Kunhong Xiao, PhD, Allegheny Health Network Cancer Institute (Establishing the mechanisms of action and preclinical efficacy of a novel BRD4- targeted therapy for diverse subtypes of metastatic castration-resistant prostate cancer.) About the Prostate Cancer Foundation The Prostate Cancer Foundation (PCF) is the world's leading philanthropic organization dedicated to funding life-saving prostate cancer research. Founded in 1993 by Mike Milken, PCF has been responsible for raising more than $1 billion in support of cutting-edge research through more than 2,250 research projects at 245 leading cancer centers, with a global footprint spanning 28 countries. Since PCF's inception, and through its efforts, patients around the world are living longer, suffering fewer complications, and enjoying better quality of all life. PCF is committed to creating a global public square for prostate cancer, in service to our mission of ending death and suffering from the disease. Learn more at pcf.org. MEDIA CONTACT: Staci L. Vernick Prostate Cancer Foundation [email protected] [email protected] 610-812-6092 SOURCE Prostate Cancer Foundation

01月08日的《热心肠日报》，我们解读了 10 篇文献，关注：饮酒，嗜酸乳杆菌，肝癌，多发性骨髓瘤，大肠癌，胰腺癌，肿瘤类器官，生殖道菌群，黑色素瘤。 NEJM：少喝酒或戒酒，可降口腔癌和食管癌风险 New England Journal of Medicine——[158.5] ① 通过分析12项口腔癌和4项食管癌研究，发现减少饮酒或戒酒可降低口腔癌和食管癌风险；② 通过分析其他癌症研究，发现减少饮酒或戒酒降低喉癌、结直肠癌和乳腺癌风险证据有限，而降低咽癌和肝癌证据不足；③ 戒酒会导致唾液乙醛浓度下降，消除上呼吸消化道和结肠局部接触与酒精相关的乙醛；④ 戒酒可导致后期外周血单个核细胞DNA染色体畸变和微核减少，口腔中乙醛-DNA加合物快速减少；⑤ 戒酒可逆转酒精使用障碍患者肠通透性增加和微生物易位。 【主编评语】 酒精饮料中的乙醇和与饮酒相关的乙醛也被归类为1类致癌物。近日New England Journal of Medicine发表最新研究，全面回顾和评估了减少饮酒和戒酒对癌症风险影响的现有证据。根据流行病学证据，特别是关于戒酒的大规模研究证据，工作组总结指出，减少饮酒或戒酒可以降低口腔癌和食管癌的发生风险，值得关注。（@九卿臣） 【原文信息】 The IARC Perspective on Alcohol Reduction or Cessation and Cancer Risk 2023-12-28, doi: 10.1056/NEJMsr2306723 于君团队：嗜酸乳杆菌或能预防脂肪肝向肝癌进展 EBioMedicine——[11.1] ① 嗜酸乳杆菌在高脂高胆固醇饲料诱导的非酒精性脂肪肝相关肝细胞癌（NAFLD-HCC）小鼠体内显著下降；② 灌胃嗜酸乳杆菌可抑制NAFLD-HCC发展；③ 嗜酸乳杆菌条件培养基可抑制NAFLD-HCC人类细胞和小鼠类器官的生长；④ 戊酸是嗜酸乳杆菌条件培养基中最富集的代谢物，并且在嗜酸乳杆菌处理的小鼠的肝脏和门静脉中证实了戊酸的上调；⑤ 戊酸与肝细胞表面受体GPR41/43结合，抑制Rho-GTPase途径，从而抑制NAFLD-HCC。 【主编评语】 非酒精性脂肪肝相关肝细胞癌（NAFLD-HCC）的全球发病率正在迅速增加，但目前缺乏针对其发展的预防措施。最近，越来越多的证据表明NAFLD-HCC和肠道微生物失调与益生菌消耗之间存在密切相关性。然而，益生菌在预防NAFLD-HCC方面的作用仍不清楚。香港中文大学于君教授团队在EBioMedicine发表最新研究进展，表明嗜酸乳杆菌在NAFLD-HCC小鼠中缺乏，而外源添加嗜酸乳杆菌可通过分泌戊酸表现出针对小鼠NAFLD-HCC肿瘤发生的保护功能，为NAFLD-HCC防治提供新思路。（@RZN） 【原文信息】 Lactobacillus acidophilus suppresses non-alcoholic fatty liver disease-associated hepatoCellular carcinoma through producing valeric acid 2024-01-03, doi: 10.1016/j.ebiom.2023.104952 健康饮食或可降低多发性骨髓瘤风险 Leukemia——[11.4] ① 纳入403538名参与者，使用4种饮食指数（HEI-2015、HDS、aMED和hPDI）进行评估，发现其中的许多分数与癌症风险和癌症死亡率呈负相关，但其与多发性骨髓瘤（MM）风险尚未清楚；② 中位随访时间15.6年间，共发生1401例MM；③ 多因素分析显示，hPDI评分与MM风险呈统计学显著负相关（HR 0.83），HEI-2015、HDS、aMED评分与MM风险之间没有显著相关性；④ 在一项敏感性分析（1331例MM病例）中，hPDI与MM风险的统计学显著降低相关。 【主编评语】 Leukemia近期发表的文章，分析NIH-AARP饮食与健康研究的数据，探究诊断前饮食模式与多发性骨髓瘤风险的相关性。（@章台柳） 【原文信息】 Pre-diagnosis dietary patterns and risk of multiple myeloma in the NIH-AARP diet and health study 2023-12-29, doi: 10.1038/s41375-023-02132-3 Lancet子刊：生殖道菌群与妇科癌症防治（综述） Lancet Microbe——[38.2] ① 女性生殖道（FGT）中的微生物种类和丰度在妇科癌症（例如宫颈癌）的发生发展中发挥作用；② 许多研究报告了人乳头瘤病毒感染和随后的宫颈癌前病变与FGT乳酸杆菌丰度下降的关联；③ 从阴道到FGT上部可观察到连续的微生物群组成，但没有证据表明调控阴道微生物群有助于改变FGT其他部分的微生物组成；④ 尽管有报道称益生元和益生菌是有益的，但这些研究规模较小，设计各异，目前还缺乏支持其在妇科癌症使用的高质量证据。 【主编评语】 女性生殖道（FGT）微生物群与妇科癌症的发生发展有关。因此，有必要研究调节FGT微生物群是否有助于预防妇科癌症。以往一些研究显示各种益生元、益生菌和其他非临床医生处方药物包括微量营养素对宫颈疾病有治疗作用。近期Lancet Microbe发表了一篇综述，本欧洲妇科肿瘤学会共识声明旨在提供当前关于FGT微生物群在妇科癌症和癌前病变中的作用的证据。总体而言，推荐益生菌、益生元或其他非处方补充剂用于预防妇科癌症还需要更大规模、更好设计的研究。（@注册营养师陈彬林） 【原文信息】 Genital tract microbiota composition profiles and use of prebiotics and probiotics in gynaecological cancer prevention: review of the current evidence, the European Society of Gynaecological Oncology prevention committee statement 2023-12-20, doi: 10.1016/S2666-5247(23)00257-4 Cell子刊：黑色素瘤和菌群的关联（综述） Cancer Cell——[50.3] ① 肠道菌群对黑色素瘤和癌症免疫监测的影响已得到充分证实，并对临床结局产生持续的影响；② 宿主-微生物的相互作用可以通过使用“组学”技术来破译，并将指导患者分层和以微生物群为中心的干预措施的发展；③ 然而，全面描述肠道、皮肤、尿液和肿瘤内微生物组学、对肠道微生态失调进行准确的检测以及合理设计以微生物群为中心的干预措施都是重大挑战；④ 未来对黑色素瘤微生物群的全面了解有可能使全世界的患者受益。 【主编评语】 在过去的十年中，肠道微生物群的组成已被发现与接受免疫治疗的癌症患者的预后相关。近期发表于Cancer Cell的一篇综述回顾了黑素瘤背景下微生物群领域的现状，最近在定义微生物作用模式方面的突破，以及如何调节微生物群以增强对癌症免疫治疗的反应。此外，还讨论了推进该领域所需的努力和目前的知识差距。（@注册营养师陈彬林） 【原文信息】 Melanoma and microbiota: Current understanding and future directions 2023-12-28, doi: 10.1016/j.ccell.2023.12.003 Nature子刊：KRAS等位基因失衡促进大肠癌发生 Nature Communications——[16.6] ① 突变型和野生型KRAS的等位基因平衡影响小鼠肠道稳态，等位基因失衡加剧了特定的癌症相关表型；② 野生型Kras的缺失加剧了通过MAPK的致癌Kras信号传导，从而驱动肿瘤的发生；③ 在体内没有外源性WNT突变的情况下，野生型Kras的缺失增强了KRASG12D的致癌作用，同时偶然诱导了对MEK1/2抑制的敏感性；④ KRASG12D驱动的结直肠癌侵袭性模型中，野生型等位基因的缺失显著改变了肿瘤进展，并通过调节免疫微环境抑制转移。 【主编评语】 KRAS基因属于Ras基因家族，其编码的KRAS蛋白通过激活下游信号通路参与细胞增殖、分化及凋亡等生命活动的调控。某些KRAS基因突变会引起KRAS蛋白过度表达和持续活化，进而过度激活下游信号通路，导致细胞不可控制地增殖恶变，最终造成组织癌变。然而，野生型KRAS在肿瘤发生和治疗反应中的作用仍有待明确。Nature Communications上近期发表的文章，发现野生型Kras的缺失促进和加速了肿瘤的发生，但极大地改变了结直肠癌中的肿瘤进化。（@RZN） 【原文信息】 KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo 2024-01-02, doi: 10.1038/s41467-023-44342-4 国内团队：NSD2过表达或促大肠癌转移 PNAS——[11.1] ① 鉴定出一种NSD2，负责将组蛋白3第36位赖氨酸二甲基化组蛋白甲基转移酶，在转移性肿瘤中过表达；② NSD2过表达在体内外均能增强肿瘤转移，发现NSD2通过激活Rac1信号促进肿瘤转移；③ 机制上，NSD2结合并激活T淋巴瘤的侵袭和转移1 (Tiam1)，通过甲基化Tiam1的K724位点促进Rac1信号传导；④ Tiam1 K724甲基化可作为癌症预后的预测因子和转移抑制的潜在靶点；⑤ 还开发了抑制肽，通过阻断NSD2和Tiam1之间的相互作用可抑制肿瘤转移。 【主编评语】 转移是肿瘤治疗失败和死亡的主要原因，然而，靶向转移种植和定植仍然是一个重大的挑战。近日，华中科技大学王桂华、胡俊波、电子科技大学许川及团队在PNAS发表最新研究，探讨了NSD2介导的Tiam1在K724位点的甲基化是否激活Rac1信号并促进肿瘤转移。更重要的是，Tiam1 K724甲基化预测癌症预后，抑制NSD2介导的Tiam1甲基化在体外和体内抑制肿瘤转移，值得关注。（@九卿臣） 【原文信息】 Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis 2023-12-19, doi: 10.1073/pnas.2305684120 Cell子刊：用患者肿瘤类器官助力转移性大肠癌精准医疗 Cell Reports Medicine——[14.3] ① 对新诊断或复发性结直肠癌社区患者实施了标准化的肿瘤类器官（PDTO）药物测试平台，从167名患者获得169份结直肠癌组织样本；② PDTO药物测试平台在预测药物反应方面显示出85％的准确性，并显示与无进展存活率有关；③ 在高通量成像平台上对PDTO进行药物敏感性测试显示，单药和联合治疗的药物反应各不相同；④ 肝转移是最佳采样部位，68.8%的病例可在7周内完成检测；⑤ PDTO药物批量测试可以为各种mCRC的标准护理疗法提供预测信息。 【主编评语】 患者源性肿瘤类器官（PDTOs）的预测性药物测试为转移性结直肠癌（mCRC）的个性化治疗带来希望，但前瞻性数据仅限于化疗方案，结果相互矛盾。近日，沃尔特与伊丽莎·霍尔医学研究所研究人员在Cell Reports Medicine发表最新研究，对新诊断或复发性结直肠癌社区患者实施了标准化的PDTO药物测试平台，发现肿瘤类器官药物批量测试可为多种mCRC标准治疗提供预测信息，值得关注。（@九卿臣） 【原文信息】 Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer 2023-12-19, doi: 10.1016/j.xcrm.2023.101335 Cell子刊：胰腺癌类器官平台鉴定出针对突变 KRAS 的特异性抑制剂 Cell Stem Cell——[23.9] ① 利用一系列野生型（WT）或含有常见PDAC驱动突变的等基因小鼠胰腺类器官开发出一个高通量药物筛选平台；② 筛选6000多种化合物，鉴定出马来酸哌己西林，它可以在体外和体内抑制携带KrasG12D突变的胰腺类器官和原代人类PDAC类器官的生长并诱导细胞死亡；③ 胆固醇合成途径在KRAS突变类器官中特异性上调，包括关键的胆固醇合成调节因子SREBP2；④ 马来酸哌己西林降低SREBP2的表达水平，并逆转KRAS突变体诱导的胆固醇合成途径的上调。 【主编评语】 KRAS突变主要是G12D和G12V，在90%以上的胰腺导管腺癌（PDAC）病例中出现。Cell Stem Cell近期发表的文章，开发出一组含有常见PDAC驱动突变的等基因小鼠胰腺类器官，来筛选KRAS突变抑制剂，并确定马来酸哌己西林可以通过下调KRAS突变特异性诱导的胆固醇生物合成途径来靶向KRAS突变。（@章台柳） 【原文信息】 A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS 2023-12-26, doi: 10.1016/j.stem.2023.11.011 JAMA子刊：50岁以下无症状成年人的结直肠癌癌症和腺瘤患病率 JAMA Network Open——[13.8] ① 纳入296170例接受结肠镜筛查的患者，其中11103例为50岁以下；② 50岁以下患者中，1166人（10.5%）患有腺瘤，389人（3.9%）至少患有一次晚期腺瘤，而在>=50岁人群中，这两种疾病比例是63884人（21.9%）、19680人（6.9%）；③ 从2008年到2018年，50岁以下的腺瘤患病率从12.4%变化到14.1%，50岁以上从21.8%到28.2%，晚期腺瘤患病率50岁以下4.0%到5.2%，50岁以上7.3%到6.8%。 【主编评语】 结直肠癌（CRC）在年轻人中的发病率正在增加。JAMA Network Open近期发表的文章，发现1988年以后，澳大利亚50岁以上患者的CRC发病率增加，而在50岁以下的患者中，男性发病率增加但女性发病率下降。所有年龄组的腺瘤患病率都有所上升，而晚期腺瘤患病率在50岁以下患者中有所上升，但在50岁及以上患者中有所下降。（@章台柳） 【原文信息】 Colorectal Cancer and Precursor Lesion Prevalence in Adults Younger Than 50 Years Without Symptoms 2023-12-06, doi: 10.1001/jamanetworkopen.2023.34757 感谢本期日报的创作者：九卿臣，RZN，章台柳，湖人总冠军，注册营养师陈彬林 点击阅读过去10天的日报： 01-07 | 人工智能火热，ChatGPT能否取代营养师？ 01-06 | 国内团队Nature子刊：用益生菌改善功能性消化不良 01-05 | 今日Science：新策略！减轻菌群相关的癌症免疫治疗副作用 01-04 | 傅静远等Nature突破：在遗传互作层面揭示血型与肠菌的密切关系 01-03 | 初波/朱书/柴人杰/顾伟等Nature子刊：肠菌代谢物促大肠癌的新机制 0 1-02 | 双重作用：65分综述深度探讨肠炎中的一类免疫细胞 01-01 | 12月，最值得看的40篇肠道健康文献！ 2023-12-31 | 26页综述详解：浆果的健康作用和食品价值 2023-12-30 | 多吃还是少吃？10文聚焦食欲调控的奥秘 2023-12-29 | 22页《自然·综述》讲透自闭症与胃肠道的关系

转移是肿瘤治疗失败和死亡的主要原因。然而，靶向转移种植和定植仍然是一个重大的挑战。2023年12月19日，华中科技大学王桂华、胡俊波及电子科技大学许川共同通讯在PNAS 上在线发表题为“Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis”的研究论文，该研究鉴定了NSD2，一种负责将组蛋白3第36位赖氨酸二甲基化的组蛋白甲基转移酶，在转移性肿瘤中过表达。NSD2过表达在体外和体内均能增强肿瘤转移。进一步分析发现，NSD2通过激活Rac1信号促进肿瘤转移。在机制上，NSD2结合并激活Tiam1 ( T淋巴瘤的侵袭和转移1 )，并通过甲基化Tiam1的K724位点促进Rac1信号传导。体内和体外研究表明，Tiam1 K724甲基化可作为癌症预后的预测因子和转移抑制的潜在靶点。此外，研究人员还开发了抑制肽，通过阻断NSD2和Tiam1之间的相互作用来抑制肿瘤转移。总之，该结果表明，NSD2甲基化的Tiam1促进Rac1信号传导和癌症转移。这些结果为抑制肿瘤转移提供了新的思路。癌症在远处器官的转移是导致癌症治疗失败和死亡的主要原因，尽管对癌症生物学进行了广泛的研究，但仍然是一个重大的挑战。为了侵入远处部位，癌细胞必须获得运动和侵袭特性，使其能够转移到血液中运输到远处器官。然而，尽管许多癌细胞具有侵袭性，但大多数在转移过程中不会存活，只有少数会成功定植于远处器官。癌细胞侵袭受到控制细胞骨架动态、细胞-基质周转、细胞-细胞连接和迁移到邻近组织的信号通路的调节。在正常细胞和癌细胞中已经确定了几种细胞运动的机制，包括细胞粘附和细胞骨架动力学的调节。了解这些机制提高了我们对控制转移细胞的移动性和可塑性的生物学原理的认识，并确定了可能阻止或可能逆转癌症转移的分子治疗的潜在靶点。因此，虽然在了解癌症转移的分子基础方面取得了进展，但仍需要更多的工作来靶向转移灶和定植，并为癌症患者开发有效的治疗方法。Rac1 ( Ras相关的C3肉毒素底物1)是小GTP结合蛋白Ras超家族中的一种GTP酶。它在多种细胞过程中发挥作用，包括细胞增殖、存活、细胞骨架动力学、细胞运动、活性氧的产生和炎症反应等。Rac1的失调和突变已在多种实体恶性肿瘤中观察到，并与不良预后相关。因此，靶向Rac1和/或其效应分子有可能抑制肿瘤进展。作为一种GTP酶，Rac1具有分子开关的功能，当与GTP (鸟苷三磷酸)结合时具有活性，当与GDP ( 5 ' -二磷酸鸟苷)结合时无活性。Rac1信号的激活受到多种抑制剂的调控，包括GTP酶激活蛋白质类( GAPs )和鸟嘌呤核苷酸解离抑制剂，以及多种激活剂，包括鸟嘌呤核苷酸交换因子( GEFs )。T淋巴瘤侵袭转移基因1 ( T lymphoma invasion and metastasis 1，Tiam1 )是作用于Rac1上游的癌基因，是Rac1的GEF，调节Rac1介导的信号通路的激活。这些通路包括细胞极性、迁移、粘附、癌变和转移。因此，靶向Tiam1或Rac1介导的信号通路可能为癌症治疗提供一条潜在的途径。蛋白质甲基化是一种重要的翻译后修饰，调节染色质特性和基因表达谱，以及各种细胞过程，如DNA复制、肿瘤起始和转移、肿瘤免疫逃逸和耐药性。此外，非组蛋白的甲基化在调节细胞信号和功能中起着至关重要的作用。例如，肿瘤抑制因子p53在K372位点被甲基转移酶SET9甲基化激活其转录功能，而SMYD2介导的p53在K370位点的甲基化则发挥相反的作用。同样，Rb蛋白的甲基化是诱导细胞周期停滞、衰老和分化的核心修饰之一。此外，NF-κB p65亚基K218 / 221位点的可逆性赖氨酸甲基化和去甲基化分别调控NF - κ B信号通路的激活和抑制。NSD2表达增加促进肿瘤转移（图源自PNAS ）NSD2，也称为MMSET ( T ( 4；14 ) MM过表达多发性骨髓瘤SET结构域蛋白)或WHSC1 ( Wolf -赫希霍恩综合征候选基因- 1)，是负责组蛋白H3第36位赖氨酸二甲基化的组蛋白甲基转移酶。NSD2通过影响染色质重塑过程和改变核小体结构，影响多种基因的转录表达水平及其相应的功能。NSD2在t( 4；14 ) ( p16；q32)易位型多发性骨髓瘤中显著高表达，且与不良预后相关。NSD2的过表达也发生在其他血液系统恶性肿瘤中，如急性淋巴细胞白血病，并在其发生、发展和恶性转化中发挥关键作用。在实体肿瘤中，NSD2通过激活AKT，使NSD2在S172位点磷酸化，抑制其泛素化，通过正反馈环路稳定NSD2蛋白，从而调节前列腺癌的侵袭和转移。NSD2的表达还与前列腺癌中的免疫细胞浸润有关，靶向抑制NSD2可能使接受免疫治疗的患者获益。在结直肠癌中，NSD2促进血管生成并导致不良预后。基于此，该研究探讨了NSD2介导的Tiam1在K724位点的甲基化是否激活Rac1信号并促进肿瘤转移。更重要的是，Tiam1 K724甲基化预测癌症预后，抑制NSD2介导的Tiam1甲基化在体外和体内抑制肿瘤转移。参考文献:Song D, Hu F, Huang C,  et al. Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis. Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2305684120. doi: 10.1073/pnas.2305684120. Epub 2023 Dec 19. PMID: 38113258.责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~