Sánchez-Castillo Anaís, Heylen Elien, Hounjet Judith, Savelkouls Kim G, Lieuwes Natasja G, Biemans Rianne, Dubois Ludwig J, Reynders Kobe, Rouschop Kasper M, Vaes Rianne D W, De Keersmaecker Kim, Lambrecht Maarten, Hendriks Lizza E L, De Ruysscher Dirk K M, Vooijs Marc, Kampen Kim R
Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven, and Leuven Cancer Institute (LKI), Herestraat 49, 3000, Leuven, Belgium.
Br J Cancer. 2024 Mar;130(4):568-584. doi: 10.1038/s41416-023-02553-y. Epub 2023 Dec 30.
Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy.
We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures.
Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels.
Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.
肺癌是最致命的癌症，85%的病例被归类为非小细胞肺癌（NSCLC）。代谢重编程是一种导致治疗耐药的癌症标志，目前对放疗后丝氨酸/甘氨酸途径适应性缺乏深入了解。
我们使用基于质谱的代谢组学分析了NSCLC患者血浆和细胞系中的放疗反应。通过增殖、克隆形成和球体形成试验研究了丝氨酸/甘氨酸转化抑制剂舍曲林与放疗联合的疗效，并在体内使用丝氨酸/甘氨酸依赖性NSCLC小鼠模型评估肿瘤生长、代谢物和细胞因子水平以及免疫特征。
在NSCLC患者和细胞模型中，放疗后丝氨酸/甘氨酸途径代谢物显著消耗。舍曲林与放疗联合使用会损害NSCLC的增殖、克隆形成能力和干细胞自我更新能力。在体内，仅在舍曲林加放疗联合治疗组中NSCLC肿瘤生长受到抑制。肿瘤重量与全身丝氨酸/甘氨酸途径代谢物水平相关，在联合治疗组中受到抑制。有趣的是，联合治疗通过与自然杀伤细胞相关的细胞因子重塑肿瘤微环境，这得到免疫检查点半乳糖凝集素-1的消除和颗粒酶B水平升高的支持。
我们的研究结果表明，使用舍曲林靶向丝氨酸/甘氨酸代谢可限制癌细胞从放疗中恢复，并通过免疫调节在NSCLC中实现肿瘤控制。
