Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain.
Immunology Department, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain.
Cell Death Dis. 2024 Jul 27;15(7):534. doi: 10.1038/s41419-024-06923-z.
Lymphoid 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. 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. 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. 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. 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.
淋巴肿瘤患者通常对标准疗法产生耐药性，或者在缓解后复发。复发是由肿瘤起始细胞（TIC）驱动的，TIC 是肿瘤细胞的一个亚群，能够重新生长肿瘤，并且对治疗具有高度耐药性。在 3D 凝胶中培养细胞是一种识别肿瘤发生细胞的方法，因为它与肿瘤发生强烈相关。TIC 而不是分化的肿瘤细胞在 3D 凝胶中生长的发现为揭示 TIC 特异性信号通路和各种癌症类型共有的治疗靶点提供了独特的机会。在这里，我们表明，在 3D 凝胶中培养淋巴样细胞会触发活性氧（ROS）的产生，导致非肿瘤性淋巴样细胞死亡，同时使淋巴瘤/白血病细胞的一部分、TIC 或 TIC 样细胞得以存活和增殖。抗氧化剂 N-乙酰半胱氨酸的治疗抑制了这种致死性，并促进了原发性非肿瘤性淋巴样细胞在 3D 凝胶中的生长。一部分淋巴瘤细胞，其特征是抗氧化剂谷胱甘肽的丰度增加，逃避了 ROS 诱导的致死性，而这种反应在非肿瘤细胞中没有出现。通过药理学抑制谷氨酸半胱氨酸连接酶（GCL），即催化谷胱甘肽生物合成限速步骤的酶，或通过敲低 GCL 催化亚基，减少淋巴瘤细胞中的谷胱甘肽产生，要么通过药理学抑制 GCL，要么通过敲低 GCL 催化亚基，都能显著减少 3D 凝胶和异种移植物中的细胞生长。来自 B 细胞淋巴瘤/白血病患者和 λ-MYC 小鼠（一种 B 细胞淋巴瘤小鼠模型）的肿瘤细胞过度产生谷胱甘肽。重要的是，药理学 GCL 抑制阻碍了雌性 λ-MYC 小鼠中的淋巴瘤生长，这表明这种治疗方法有望成为女性淋巴瘤/白血病患者的一种治疗策略。
