Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, 38123, Trento, Italy.
Laboratory of Stem Cell Biology, Department CIBIO, University of Trento, 38123, Trento, Italy.
Nat Commun. 2022 Aug 15;13(1):4767. doi: 10.1038/s41467-022-32448-0.
Pediatric and adult high-grade gliomas are the most common primary malignant brain tumors, with poor prognosis due to recurrence and tumor infiltration after therapy. Quiescent cells have been implicated in tumor recurrence and treatment resistance, but their direct visualization and targeting remain challenging, precluding their mechanistic study. Here, we identify a population of malignant cells expressing Prominin-1 in a non-proliferating state in pediatric high-grade glioma patients. Using a genetic tool to visualize and ablate quiescent cells in mouse brain cancer and human cancer organoids, we reveal their localization at both the core and the edge of the tumors, and we demonstrate that quiescent cells are involved in infiltration of brain cancer cells. Finally, we find that Harmine, a DYRK1A/B inhibitor, partially decreases the number of quiescent and infiltrating cancer cells. Our data point to a subpopulation of quiescent cells as partially responsible of tumor invasiveness, one of the major causes of brain cancer morbidity.
儿童和成人高级别神经胶质瘤是最常见的原发性恶性脑肿瘤，由于治疗后的复发和肿瘤浸润，预后不良。静止细胞与肿瘤复发和治疗耐药有关，但它们的直接可视化和靶向仍然具有挑战性，阻碍了对其机制的研究。在这里，我们在儿童高级别神经胶质瘤患者中鉴定出一群表达 Prominin-1 的非增殖状态的恶性细胞。使用一种遗传工具来可视化和消融小鼠脑癌和人类癌症类器官中的静止细胞，我们揭示了它们在肿瘤核心和边缘的定位，并证明静止细胞参与了脑癌细胞的浸润。最后，我们发现 Harmine，一种 DYRK1A/B 抑制剂，可部分减少静止和浸润性癌细胞的数量。我们的数据表明，静止细胞亚群是肿瘤侵袭性的部分原因之一，而肿瘤侵袭性是脑癌发病率的主要原因之一。
