HBEGF

引言在儿童癌症的隐秘战场上，高危神经母细胞瘤（high-risk neuroblastoma）或许是“最狡猾的幸存者”——即便经历化疗的重击，仍有半数患者在五年内复发。这些肿瘤究竟如何在治疗后悄然反扑？它们的“逃生秘籍”是否藏在肿瘤细胞的身份转换中，或是微环境盟友的暗中助力？答案正逐渐浮出水面。4月14日《Nature Genetics》发布的“Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring”首次通过单细胞多组学技术（single-cell multiomics）动态捕捉了22名高危患儿化疗前后的肿瘤演变图谱。通过分析超过130万个细胞的基因表达、染色质开放性和基因组特征，科学家发现化疗如同一场“细胞进化筛选”：原本占主导的肾上腺能肿瘤细胞（ADRN样）被大量清除，而残余的癌细胞却悄然转向两种生存策略——高度分化的神经元样细胞以“休眠”状态蛰伏，或激活间充质样（MES样）基因模块提升耐药性。更令人警惕的是，间充质样细胞在部分患者中疯狂扩增，其比例与治疗失败的风险正相关，如同肿瘤为自己建造的“铜墙铁壁”。而这场“耐药革命”的幕后推手，竟是一群“叛变”的免疫细胞——巨噬细胞。化疗后，这些本应抗击肿瘤的战士集体倒戈，转而释放生长因子HB-EGF，与癌细胞表面的ERBB4受体结合，激活促存活的ERK信号通路。当研究者通过基因编辑阻断这一通路时，小鼠体内肿瘤的生长速度骤降。空间组学更揭示了触目惊心的细节：携带ERBB4的癌细胞与分泌HB-EGF的巨噬细胞在组织内形成“共生巢穴”，其贴近程度远超普通细胞，仿佛在进行一场暗度陈仓的“分子交易”。癌细胞的“变形战记”：肾上腺能→间充质的致命转身神经母细胞瘤的可怕之处，在于它保留了胚胎神经嵴细胞的“变形能力”。当化疗药物来袭时，这种古老的发育程序被重新唤醒——在对单细胞转录组的深度解析中，科学家捕捉到了癌细胞身份的“动态转换路线图”：身份转换的分子密码：ADRN→MES的启动开关：约三成的残余细胞在化疗后表达间充质关键转录因子TWIST1和YAP1，其染色质开放区域与ADRN细胞相比，富集了TGF-β通路调控元件（如SMAD3结合基序）。耐药护盾机制：MES样细胞的整合素α5/β1（ITGA5/ITGB1）表达量提升，通过与细胞外基质的胶原纤维结合，形成阻止药物渗透的物理屏障。发育程序的“逆向重启”：单细胞轨迹分析揭示，部分MES样细胞能重返胎儿期神经嵴干细胞的原始状态，并进入休眠状态躲避化疗追杀。微环境暗战：巨噬细胞的“反叛协议”如果说癌细胞是这场生存游戏的主角，那么肿瘤微环境中的巨噬细胞，则扮演了关键“反派配角”。令人意外的是，原本负责清理癌细胞的巨噬细胞，在化疗后竟集体倒戈！单细胞免疫图谱显示：表型切换：化疗后，M2型促肿瘤巨噬细胞数值飙升（细胞表达CD206+CD163+），其血管生成基因（VEGFA）表达量翻倍，而抗肿瘤的M1型标志物则有所下降。致命交易链：空间转录组技术（10x Visium）捕获到一个精密的信号网络——携带ERBB4受体的癌细胞与分泌肝素结合表皮生长因子（HB-EGF）的巨噬细胞形成“共生巢穴”。在1mm²区域内，这对“危险CP”的空间共定位概率达到惊人的37.5%，是普通细胞间的7.3倍！动物模型验证：当研究者使用基因编辑敲除巨噬细胞的HB-EGF后，荷瘤小鼠对化疗的敏感度提升了4倍（肿瘤缩小速度从每天1.2mm³增至5.1mm³）。更有意思的是，若将ERBB4阳性细胞单独移植，其成瘤率不足20%；但当同时注射HB-EGF+巨噬细胞时，这一比例将会暴增！耐药堡垒的构建法则：空间生态的致命棋局在化疗后的肿瘤中，癌细胞、基质细胞和免疫细胞如同共同编织了一张三维生存网。空间多组学（CODEX成像+CosMx SMI）揭露了更多隐秘合作：神经元庇护网：残留的神经元样癌细胞与Schwann细胞（神经胶质细胞）形成微型神经网络，通过分泌生长因子维持休眠状态，并在局部区域富集保护性胶原（I型胶原纤维密度提升约180%）。成纤维细胞陷阱：活化的成纤维细胞（α-SMA+）通过旁分泌LOXL2重塑基质硬度，迫使癌细胞激活机械敏感通道PIEZO1，进而触发促转移基因（MMP2、CXCR4）。代谢军备竞赛：微环境中的乳酸在化疗后浓度飙升，迫使巨噬细胞转向糖酵解模式，而癌细胞则通过代谢分流（glutamine消耗量增加）获取生存优势。翻译作弊机制：MES样细胞的核糖体生物发生调控因子DRG1上调数倍，通过加速蛋白质翻译（每分钟多合成1200个氨基酸），在化疗应激下快速生产抗凋亡蛋白（BCL-2、MCL-1）。破局武器库：从分子靶点到生态干预面对化疗引发的耐药进化网，科学家正开发基于多维度打击的新型策略：瞄准关键生命线——HB-EGF/ERBB4轴：基因敲除实验：抑制ERBB4信号（通过shRNA敲低）可使化疗耐药肿瘤的侵袭性降低（Transwell迁移实验，P<0.01）。靶向TWIST1的反义寡核苷酸：可抑制MES表型转化（MES标志物VIM表达下降），并增强肿瘤对化疗的敏感性。机制证据：在化疗后肿瘤中，抑制整合素β1（ITGB1）可破坏癌细胞-胶原的黏附，使阿霉素的瘤内浓度增加。癌症治疗的“生态战”启示录神经母细胞瘤的化疗耐药研究揭示了一个核心真理：癌症不仅是基因突变的产物，更是细胞群体在微环境中上演的“演化生存剧”。当我们在实验室培养皿中研究癌细胞时，往往忽略了这场大戏的真正舞台——由数十种细胞、机械信号和代谢梯度构成的三维生态系统。未来的抗癌战役需要更高维的思维。或许在某一天，“癌症治疗范式”将从传统的“杀伤最大化”转向“生态调控”。在这场生命的终极博弈中，人类正将癌症的“黑暗智慧”转化为治疗的新曙光。参考文献Yu, W., Biyik-Sit, R., Uzun, Y., Chen, C. H., Thadi, A., Sussman, J. H., Pang, M., Wu, C. Y., Grossmann, L. D., Gao, P., Wu, D. W., Yousey, A., Zhang, M., Turn, C. S., Zhang, Z., Bandyopadhyay, S., Huang, J., Patel, T., Chen, C., ... Tan, K. (2025). Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring. Nature Genetics责编|探索君排版|探索君转载请注明来源于【生物探索】声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！End往期精选围观Nature | 靶向线粒体VDAC2：破解实体瘤免疫治疗抵抗的"死亡密钥"热文Nature Medicine | 多囊女性子宫内膜藏着什么秘密？——全球首份单细胞图谱揭示治疗新方向热文Nature | 颠覆认知！大脑学习的惊人秘密：你的“潜伏知识”是如何瞬间爆发的？热文Cell | 颠覆认知！染色体形成并非依赖“骨架”，自组织模型重塑教科书热文Science | 为什么我们回想不起三岁前的经历?

Study offers first in-depth analysis of the microenvironment of neuroblastoma and its response to chemotherapy PHILADELPHIA, April 14, 2025 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) developed a longitudinal atlas of neuroblastoma, a common and potentially deadly childhood cancer, to gain deeper understanding into precise molecular mechanisms underlying why and how certain treatments eventually become ineffective. The findings, which offer insights that could potentially lead to new personalized medicine approaches in neuroblastoma treatment, were published today in the journal Nature Genetics. Despite significant advances in the standard of care, the 5-year survival rate of high-risk neuroblastoma after diagnosis remains less than 50%. Neuroblastoma cells within the same tumor can vary greatly, which creates challenges in treatment efficacy. Until now, the scientific community lacked understanding of how the tumor microenvironment changes during treatment. In this study, researchers created a cell atlas that afforded the first in-depth look at how different cell types, like malignant cells and immune cells, interact and change within their natural environment, which led to valuable new insights. "Our atlas provides a crucial foundation for developing novel treatments by mapping the complex interactions between malignant cells and surrounding cells that support tumor growth," said senior study author Kai Tan, PhD, a professor in the Department of Pediatrics at Children's Hospital of Philadelphia who spearheads CHOP's participation in the National Cancer Institute (NCI) Human Tumor Atlas Network (HTAN). "As researchers, we look to use these insights to tailor therapies to target unique characteristics of a patient's tumor. Overall, we are optimistic about the doors our research and techniques are opening." In this study, CHOP researchers used advanced single cell sequencing and spatial omics techniques to analyze the transcriptional, epigenetic and proteomic profiles of tumor samples from 22 pediatric patients with high-risk neuroblastoma before and after induction chemotherapy. This multidimensional dataset can be accessed from the HTAN data portal. The authors uncovered diverse tumor and non-tumor cell characteristics, as well as major changes in these characteristics following chemotherapy. They found that patients had worse outcomes when cancer cells were multiplying more actively and became more metabolically active. Conversely, tumors that developed more mature, neuron-like features resulted in better outcomes in patients. Additionally, researchers found that an increase in a type of mesenchymal-like tumor cells was linked to poorer responses in chemotherapy. Certain immune cells (e.g. macrophages) became more active in ways that led to tumor growth by enabling blood vessel growth while suppressing the immune response. Researchers also discovered a specific communication pathway (HB-EGF/ERBB4) between macrophages and cancer cells that triggered signals promoting tumor growth. These findings highlight the importance of identifying new factors inside the tumor's microenvironment that influence how high-risk neuroblastoma responds to treatment. Using preclinical models, the researchers are further testing this pathway with the goal of eventually translating the findings to novel therapeutic strategies. "Studies of this magnitude are only made possible by monumental team efforts," said Wenbao Yu, PhD, a lead author of the study and a Research Assistant Professor at Children's Hospital of Philadelphia. "With the collaboration of biologists, clinicians, and computational scientists, we were able to gain new insights into the complex ecosystem of neuroblastoma."   The research was supported by the National Cancer Institute (NCI) Human Tumor Atlas Network grant under award (#U2C CA233285). Additional support includes National Institutes of Health (NIH) grant (U54 HL165442), American Cancer Society Institutional Research Grant (IRG-22-150- 41-IRG) and NIH grant (T32 CA009140). Yu et al. "Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring. Nature Genetics. Online April 14, 2025. DOI: 10.1038/s41588-025-02158-6. About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Jennifer Lee Children's Hospital of Philadelphia (267) 426-6084 [email protected] SOURCE Children's Hospital of Philadelphia WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

点击蓝字 关注我们 Helicobacter pylori CagA elevates FTO to induce gastric cancer progression via a “hit-and-run” paradigm Bing He, Yiyang Hu, Yuyun Wu, Chao Wang, Limin Gao, Chunli Gong, Zhibin Li, Nannan Gao, Huan Yang, Yufeng Xiao, Shiming Yang Cancer Communications. 2025 https://doi.org/10.1002/cac2.70004 研究亮点 1. 揭示了CagA通过m6A调节因子FTO促进胃癌进展的分子机制； 2. 从表观遗传学角度，深入阐明了CagA诱导胃癌进展的 “肇事逃逸” 机制； 3. 证实FTO特异性抑制剂甲氯芬那酸(MA)联合幽门螺杆菌根除治疗可显著抑制胃癌转移。 研究简介 陆军军医大学第二附属医院杨仕明教授团队最新研究发现，幽门螺杆菌（H. pylori）通过释放毒力因子CagA，促进m6A去甲基化酶FTO的表达，从而增强胃癌的转移潜力。研究者证实，CagA通过转录因子JUN上调FTO表达，下调EMT相关分子HBEGF m6A修饰水平，进而阻止YTHDF2依赖的HBEGF mRNA降解。此外，根除H. pylori无法逆转CagA诱导的FTO和HBEGF水平的升高。值得注意的是，FTO特异性抑制剂MA 治疗能够抑制胃癌细胞发生EMT，并在动物模型和人体胃癌类器官中展现出抑制胃癌转移的效果。这些发现不仅表明FTO抑制剂有望成为胃癌治疗的新型药物，还为CagA诱导胃癌进展的“肇事逃逸”机制提供了表观遗传学层面的新见解。 图文导读 1. cagA+ H. pylori 感染降低胃癌m6A修饰，促进FTO表达 研究团队分析了胃癌组织和细胞中的m6A水平，发现cagA+ H. pylori感染显著降低了m6A 水平，同时促进了m6A 去甲基化酶FTO的表达。进一步研究表明，胃癌组织中FTO的高表达与患者不良预后密切相关。 2. cagA+ H. pylori 感染增强胃癌细胞的迁移能力依赖于FTO 研究者对FTO敲低的RNA-seq数据进行功能分析，发现差异基因中上皮-间质转化(EMT)相关的基因显著富集。体外功能实验证实FTO以依赖其m6A酶活性的方式增强胃癌细胞的迁移和侵袭潜能。此外，研究进一步证实cagA+ H. pylori 感染增强胃癌细胞的迁移和侵袭能力依赖于FTO。 3. CagA通过JUN上调FTO的转录 鉴于CagA能够上调FTO的mRNA和蛋白水平，但不影响其mRNA稳定性，研究人员推测CagA可能在转录水平调控FTO表达。数据库预测联合ChIP等系列实验证实cagA+ H. pylori 感染通过激活JUN促进FTO转录。 4. CagA-FTO轴以m6A依赖的方式调控EMT相关分子HBEGF的表达 为探索CagA-FTO轴促进胃癌转移的分子机制，研究者通过MeRIP-seq、 RNA-seq等一系列分析发现cagA+ H. pylori 感染降低EMT相关分子HBEGF的 m6A 修饰，进而促进HBEGF分泌，激活EMT并诱导胃癌转移。 5. YTHDF2识别HBEGF上的m6A修饰，降低HBEGF的mRNA稳定性 为鉴定与HBEGF结合的m6A阅读蛋白，研究者采用RNA pull-down、质谱分析和RIP等实验方法，筛选并验证了YTHDF2可识别HBEGF上的m6A位点，从而降低其mRNA稳定性。此外，突变HBEGF的m6A修饰位点后，FTO和 YTHDF2对HBEGF的表达调控作用消失，表明FTO和YTHDF2通过m6A修饰调控HBEGF表达。 6. CagA通过“肇事逃逸”机制诱导胃癌进展，MA联合H. pylori根除显著抑制胃癌转移 “肇事逃逸”假说认为，H. pylori 根除可能无法阻止胃癌的进展。与该假说一致，研究者观察到即使根除H. pylori，CagA诱导的FTO和HBEGF的表达水平升高也无法被逆转，这表明cagA+ H. pylori 慢性感染诱导了不可逆的表观遗传学修饰改变。然而，FTO特异性抑制剂MA治疗显著降低了HBEGF表达，且MA与抗生素联合治疗可阻断CagA诱导的EMT和胃癌细胞的转移能力。 7. 体内实验验证CagA靶向FTO促进胃癌转移 研究人员通过小鼠转移瘤模型，发现FTO敲低可显著抑制胃癌细胞的肺转移，而FTO过表达导致肺部转移灶增加。此外，CagA显著促进了胃癌细胞的肺转移，但MA治疗有效地抵消了CagA对胃癌转移的促进作用。胃癌患者样本的组织芯片分析结果提示，胃癌组织中CagA和FTO的高表达与患者不良预后相关。  声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。 来源：Cancer Communications 排版：lagertha 校对：松月