AbstractLymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity.

摘要淋巴肿瘤患者通常表现出对标准疗法的抵抗力或缓解后复发。复发是由肿瘤起始细胞（TIC）驱动的，TIC是能够使肿瘤再生并且对治疗具有高度抗性的肿瘤细胞的子集。在3D凝胶中生长细胞是一种识别致瘤细胞的方法，因为它与致瘤性密切相关。

The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells.

TIC而不是分化的肿瘤细胞在3D凝胶中生长的发现为揭示各种癌症类型共有的TIC特异性信号传导途径和治疗靶标提供了独特的机会。在这里，我们显示在3D凝胶中培养淋巴样细胞会触发活性氧（ROS）的产生，导致非肿瘤淋巴样细胞死亡，同时能够使淋巴瘤/白血病细胞，TIC或TIC样细胞的一部分存活和增殖。

Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells.

用抗氧化剂N-乙酰半胱氨酸处理可抑制这种致死性，并促进3D凝胶中原代非肿瘤淋巴样细胞的生长。淋巴瘤细胞的一个子集，其特征在于抗氧化剂谷胱甘肽的丰度增加，逃脱了ROS诱导的致死性，这是在非肿瘤细胞中未见的反应。

Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts.

通过药理学抑制谷氨酸半胱氨酸连接酶（GCL）（一种催化谷胱甘肽生物合成限速步骤的酶）或通过敲除GCL催化亚基GCLC来减少淋巴瘤细胞中谷胱甘肽的产生，大大降低了3D凝胶和异种移植物中的细胞生长。

Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients..

来自B细胞淋巴瘤/白血病患者和λ-MYC小鼠（B细胞淋巴瘤小鼠模型）的肿瘤细胞过量产生谷胱甘肽。重要的是，药理学GCL抑制阻碍了雌性λ-MYC小鼠的淋巴瘤生长，这表明这种治疗有望成为女性淋巴瘤/白血病患者的治疗策略。。

IntroductionMany conventional cancer therapies often lead to undesired side effects because they target proteins and cellular processes necessary for normal cell survival and proliferation, including various progenitor cell types. Identifying genes and proteins specifically associated with tumor traits would facilitate the development of therapies that selectively target tumor cells while minimizing toxic effects.

引言许多常规癌症疗法通常会导致不希望的副作用，因为它们靶向正常细胞存活和增殖所必需的蛋白质和细胞过程，包括各种祖细胞类型。鉴定与肿瘤特征特异性相关的基因和蛋白质将有助于开发选择性靶向肿瘤细胞的疗法，同时最大程度地减少毒性作用。

Despite some potentially fatal side effects, the major failures of current cancer treatments are the lack of response in certain human cancer types and tumor relapse after initial remission [1].Despite progress in cancer research and the development of new potential therapies, >90% of cancer treatments exhibiting preclinical activity fail in human trials [2, 3].

尽管有一些潜在的致命副作用，但目前癌症治疗的主要失败是某些人类癌症类型缺乏反应，初始缓解后肿瘤复发（1）。尽管癌症研究取得了进展，并开发了新的潜在疗法，但超过90%的具有临床前活性的癌症治疗在人体试验中失败[2，3]。

This failure is largely due to testing exclusively on cancer cell lines grown in liquid medium, a condition that predicts in vivo efficacy to anticancer drugs worse than cell culture in 3D gels [4, 5] and is far from adequately reflecting the therapeutic responsiveness of cancers within their native microenvironment [2, 3].

。

Unfortunately, one-third of cancer patients succumb to the disease within five years of diagnosis, primarily due to tumor recurrence [1, 6]. Discovering strategies to prevent tumor relapse continues to be a challenge.A major challenge in developing effective anti-cancer therapies is identifying tumor-specific properties.

不幸的是，三分之一的癌症患者在诊断后五年内死于该疾病，主要是由于肿瘤复发[1，6]。发现预防肿瘤复发的策略仍然是一个挑战。开发有效的抗癌疗法的主要挑战是确定肿瘤特异性。

One such property is the altered redox state, which is observed in many forms of cancer [7]. Low levels of reactive oxygen species (ROS) mediate signaling cascades involved in cell proliferation [8], while high ROS levels can lead to DNA damage and eventual cell death [9]. To neutralize ROS, cells induce various antioxidant systems, including the activation of the p.

一个这样的性质是改变的氧化还原状态，这在许多形式的癌症中都可以观察到。低水平的活性氧（ROS）介导参与细胞增殖的信号级联反应（8），而高水平的ROS可导致DNA损伤和最终的细胞死亡（9）。为了中和ROS，细胞诱导各种抗氧化系统，包括激活p。

Data availability

数据可用性

This manuscript does not have data that need to be deposited in a public database. All data analyzed during the current study are available from the corresponding author on reasonable request.

这份手稿没有需要保存在公共数据库中的数据。本研究期间分析的所有数据均可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsThe authors would like to thank D. Trono for plasmids and H.C. Morse III and the National Institute of Allergy and Infectious Dieseases (NIH) for donating C57BL/6N-Tg(IGL-MYC)3Hm mice.FundingThe CBM is supported by Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, and is a Severo Ochoa Center of Excellence (grant CEX2021-001154-S) funded by MICIN/AEI/10.13039/501100011033.

下载参考文献致谢作者要感谢D.Trono提供质粒，感谢H.C.Morse III和美国国家过敏与传染病研究所（NIH）捐赠C57BL/6N Tg（IGL-MYC）3Hm小鼠。资助CBM得到了高等调查委员会和马德里自治大学的支持，是由MICIN/AEI/10.13039/501100011033资助的Severo Ochoa卓越中心（grant CEX2021-001154-S）。

This work was supported by Fundación de la Asociación Española contra el Cáncer (AECC) grant PROYE20060CAMP to M.R.C., grant PID2022-138880OB-I00 funded by MCIN /AEI /10.13039/501100011033 / FEDER, UE to M.L.T., grant PID2020-115218RB-I00 funded by MCIN/AEI/10.13039/501100011033 to T.I., and Instituto de Salud Carlos III (CIBERNED) to T.I.

这项工作得到了西班牙反法西斯基金会（AECC）对M.R.C.的资助PROYE20060CAMP，由MCIN/AEI/10.13039/501100011033/FEDER资助的PID2022-13880OB-I00，对M.L.T的UE，由MCIN/AEI/10.13039/501100011033资助的PID2020-115218RB-I00对T.I的资助，以及萨卢德·卡洛斯三世研究所（CIBERNED）对T.I的资助。

O.K. held an FPI fellowship from the Spanish Ministerio de Educacion y Ciencia (BES-2014-069236).Author informationAuthor notesThese authors contributed equally: Alberto H.-Alcántara, Omar Kourani.Authors and AffiliationsCell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, SpainAlberto H.-Alcántara, Omar Kourani, Patricia Martínez-Núñez, Estela Herranz-Martín & Miguel R.

O、 K.持有西班牙教育和科学部长颁发的FPI奖学金（BES-2014-069236）。作者信息作者注意到这些作者做出了同样的贡献：Alberto H.-Alcántara，Omar Kourani。作者和附属机构cell cell communication and Infinition Unit，Centro de Biología Molecular Severo Ochoa（CBM），CSIC-UAM，马德里，SpainAlberto H.-Alcántara，Omar Kourani，Patricia Martínez-Núñez，Estela Herranz MartíN＆Miguel R。

CampaneroImmunology Department, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, SpainAna Marcos-Jiménez & Cecilia Muñoz-CallejaImmune System Development and Function Unit, CBM, CSIC-UAM, Madrid, SpainPatricia Fuentes & María L. ToribioCentro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC) Madrid, Madrid, SpainCecilia Muñoz-CallejaFacultad de Medicina, Universidad Autónoma de Madrid, Madrid, SpainCecilia Muñoz-CallejaDepartment of Neurological Diseases and Aging, Instituto de Investiga.

Campaneroimmunology部门，公主健康研究所，公主大学医院，马德里，西班牙马科斯-希门尼斯和塞西莉亚·穆尼奥斯-Callejaimmune系统开发和功能股，CBM，CSIC-UAM，马德里，西班牙Muñoz-研究所神经疾病和衰老科。

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PubMed Google ScholarContributionsMRC conceived and designed the study with contributions from TI, AH-A. and OK performed most of the experiments with contributions from PM-N and EH-M.; AM-J and CM-C analyzed human samples; PF, MLT, and TI provided experimental support and ideas for the project.

PubMed Google ScholarContributionsMRC在TI，AH-A和OK的贡献下构思并设计了这项研究。大多数实验都是由PM-N和EH-M贡献的。；AM-J和CM-C分析了人类样本；PF，MLT和TI为该项目提供了实验支持和想法。

AH-A, OK and MRC analyzed the data with contributions from all other authors. MRC wrote the manuscript with contributions from AM-J, PF, MLT, CMC, and TI. All authors read and approved the final paper.Corresponding authorCorrespondence to.

AH-A，OK和MRC使用所有其他作者的贡献分析了数据。MRC在AM-J，PF，MLT，CMC和TI的贡献下撰写了手稿。所有作者均阅读并批准了最终论文。对应作者对应。

Miguel R. Campanero.Ethics declarations

米格尔·R·坎帕内罗。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics

Informed consent was obtained for the use of human samples in accordance with the Declaration of Helsinki. Experimental procedures were approved by the Institutional Board of Hospital de La Princesa (PI-802). All animal procedures were approved by the CSIC Ethics Committee (ref. 634/2017 and 1053/2021) and by the Madrid Regional authorities (ref.

根据赫尔辛基宣言，使用人体样本已获得知情同意。实验程序经公主医院机构委员会（PI-802）批准。所有动物程序均经CSIC伦理委员会（参考文献634/2017和1053/2021）和马德里地区当局（参考文献）批准。

PROEX 215/17 and 093.7/21), and conformed to EU Directive 2010/63EU and Recommendation 2007/526/EC regarding the protection of animals used for experimental and other scientific purposes, enforced in Spanish law under Real Decreto 1201/2005..

PROEX 215/17和093.7/21），并符合欧盟指令2010/63EU和关于保护用于实验和其他科学目的的动物的建议2007/526/EC，在西班牙法律中根据真正的第1201/2005号法令强制执行。。

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Reprints and permissionsAbout this articleCite this articleH.-Alcántara, A., Kourani, O., Marcos-Jiménez, A. et al. Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis.

-Alcántara，A.，Kourani，O.，Marcos Jiménez，A。等人。谷胱甘肽过量产生介导淋巴瘤起始细胞存活，并对淋巴瘤发生具有性别依赖性作用。

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