Sánchez-Castillo Anaís, Savelkouls Kim G, Baldini Alessandra, Hounjet Judith, Sonveaux Pierre, Verstraete Paulien, De Keersmaecker Kim, Dewaele Barbara, Björkblom Benny, Melin Beatrice, Wu Wendy Y, Sjöberg Rickard L, Rouschop Kasper M A, Broen Martijn P G, Vooijs Marc, Kampen Kim R
Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands.
Pole of Pharmacology, Institut de Recherche Experimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium.
Oncogenesis. 2024 Nov 13;13(1):39. doi: 10.1038/s41389-024-00540-3.
The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPH showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/gly glioblastoma models. Interestingly, ser/gly glioblastomas, including PSPH and PSPH, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/gly glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/gly cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/gly glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.
丝氨酸/甘氨酸（Ser/Gly）合成途径从糖酵解分支而来，在约30%的癌症中被过度激活。在约13%的胶质母细胞瘤病例中，我们观察到编码催化丝氨酸合成最后一步的酶PSPH的基因频繁扩增和罕见突变。这促使我们揭示PSPH基因改变及随后的Ser/Gly代谢失调在胶质母细胞瘤发病机制中的相关性。过表达PSPH的原发性胶质母细胞瘤细胞表现出克隆形成能力、细胞增殖和迁移增加，这得到了核苷酸合成增加以及还原性NAD(P)利用增加的支持。我们之前鉴定出舍曲林是Ser/Gly合成的抑制剂，并探索了其在次优剂量下与临床预测试的氯喹联合用于靶向Ser/Gly胶质母细胞瘤模型的疗效。有趣的是，包括PSPH过表达的Ser/Gly胶质母细胞瘤对联合治疗表现出选择性协同增殖抑制作用。敲低PSPH严重影响Ser/Gly胶质母细胞瘤的克隆形成能力和增殖，同时增加其对氯喹治疗的敏感性。代谢物图谱分析显示，舍曲林/氯喹联合治疗可阻断NADH和ATP生成并限制核苷酸合成，从而抑制胶质母细胞瘤增殖。我们之前的研究强调了Ser/Gly癌细胞在免疫抑制水平对其微环境的调节作用。为此，PSPH高表达预示胶质母细胞瘤患者对免疫检查点治疗反应不佳。有趣的是，我们发现胶质母细胞瘤中的PSPH扩增促进免疫抑制因子半乳凝素-1的表达，而舍曲林治疗可抑制该表达。总体而言，我们揭示了Ser/Gly胶质母细胞瘤具有增强的克隆形成能力、迁移能力和免疫系统抑制特征，联合使用舍曲林/氯喹治疗可应对这些特征，为该亚组胶质母细胞瘤患者揭示了新的治疗机会。
