美国加州大学旧金山分校David R. Raleigh课题组揭示脑膜瘤异质性和演化的空间基因组、生化和细胞机制。该研究于2024年5月17日在线发表于国际一流学术期刊《自然—遗传学》。

据悉，肿瘤内异质性是癌症演化和耐药性的基础，但人们对驱动肿瘤内异质性的靶向机制知之甚少。脑膜瘤是最常见的原发性颅内肿瘤，对所有药物疗法都有抗药性，高级别脑膜瘤具有显著的瘤内异质性。

附：英文原文

Title: Spatial genomic, biochemical and cellular mechanisms underlying meningioma heterogeneity and evolution

Author: Lucas, Calixto-Hope G., Mirchia, Kanish, Seo, Kyounghee, Najem, Hinda, Chen, William C., Zakimi, Naomi, Foster, Kyla, Eaton, Charlotte D., Cady, Martha A., Choudhury, Abrar, Liu, S. John, Phillips, Joanna J., Magill, Stephen T., Horbinski, Craig M., Solomon, David A., Perry, Arie, Vasudevan, Harish N., Heimberger, Amy B., Raleigh, David R.

Issue&Volume: 2024-05-17

Abstract: Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K–AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.

DOI: 10.1038/s41588-024-01747-1

Source: https://www.nature.com/articles/s41588-024-01747-1