Spatial Heterogeneity of Invading Glioblastoma Cells Regulated by Paracrine Factors
Spatial Heterogeneity of Invading Glioblastoma Cells Regulated by Paracrine Factors
复制标题
旁分泌因子调节侵袭胶质母细胞瘤细胞的空间异质性
DOI：
10.1089/ten.tea.2021.0168
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发表时间：
2022
影响因子：
4.1
通讯作者：
Sudo Ryo
中科院分区：
文献类型：
--
作者：
Chonan Yuta;Yamashita Tadahiro;Sampetrean Oltea;Saya Hideyuki;Sudo Ryo
胶质母细胞瘤(GBM)是成人最常见、最致命的原发恶性脑肿瘤。GBM表现为异质性肿瘤细胞群，包括具有干细胞样特征的胶质瘤起始细胞(GICs)和分化的胶质瘤细胞。在GBM细胞侵袭正常脑组织的过程中，位于侵袭前沿的GICs保持干性，而位于肿瘤核心的GICs表现为细胞分化。然而，基底膜细胞空间异质性形成的细胞分化机制仍不清楚。在目前的研究中，我们首先观察到在微流控装置中，从GICs的同基因克隆群体中出现的空间异质性的GBM细胞群体在3D胶原水凝胶中的侵袭。具体地说，侵袭前沿的GICs保持干性，而拖尾细胞表现出星形细胞分化。细胞的空间异质性是由于侵袭前线的GICs和尾随细胞密度的差异造成的。细胞密度较高时，星形胶质细胞通过分泌旁分泌因子向星形胶质细胞分化，而细胞密度较低的侵袭前沿细胞由于缺乏旁分泌因子而保持干性。此外，我们还证明了间质血流通过清除旁分泌因子抑制了拖尾GICs的星形细胞分化。我们的发现表明，肿瘤细胞之间的细胞间串扰是形成不同分化状态的GBM细胞空间细胞异质性的重要因素。这也为在侵袭前沿针对具有干细胞特征的GBM细胞的新的治疗策略的开发提供了洞察力。影响陈述我们在微流控设备中阐明了胶质母细胞瘤由胶质瘤起始细胞(GIC)和分化的胶质瘤细胞组成的空间细胞异质性的细胞分化机制。在细胞密度较高的情况下，拖尾细胞通过其产生的旁分泌因子的局部积累而表现出星形细胞分化，而在低细胞密度的侵袭前沿的细胞由于缺乏旁分泌因子而显示出保留了茎。我们的发现为开发针对侵袭前沿的GICs的有效治疗策略提供了有价值的知识。
Glioblastoma (GBM) is the most common and lethal type of malignant primary brain tumor in adults. GBM displays heterogeneous tumor cell population comprising glioma-initiating cells (GICs) with stem cell-like characteristics and differentiated glioma cells. During GBM cell invasion into normal brain tissues, which is the hallmark characteristic of GBM, GICs at the invasion front retain stemness, while cells at the tumor core display cellular differentiation. However, the mechanism of cellular differentiation underlying the formation of spatial cellular heterogeneity in GBM remains unknown. In the present study, we first observed spatially heterogeneous GBM cell populations emerged from an isogenic clonal population of GICs during invasion into a 3D collagen hydrogel in a microfluidic device. Specifically, GICs at the invasion front maintained stemness, while trailing cells displayed astrocytic differentiation. The spatial cellular heterogeneity resulted from the difference in cell density between GICs at the invasion front and trailing cells. Trailing GICs at high cell density exhibited astrocytic differentiation through local accumulation of paracrine factors they secreted, while cells at the invasion front of low cell density retained stemness due to the lack of paracrine factors. In addition, we demonstrated that interstitial flow suppressed astrocytic differentiation of trailing GICs by the clearance of paracrine factors. Our findings suggest that intercellular crosstalk between tumor cells is an essential factor in developing the spatial cellular heterogeneity of GBM cells with various differentiation statuses. It also provides insights into the development of novel therapeutic strategies targeting GBM cells with stem cell characteristics at the invasion front.Impact StatementWe elucidated the mechanism of cellular differentiation underlying the spatial cellular heterogeneity of glioblastoma composed of glioma-initiating cells (GICs) and differentiated glioma cells during invasion in a microfluidic device. Trailing cells at high cell density exhibited astrocytic differentiation through local accumulation of paracrine factors they produced, while cells at the invasion front of low cell density were shown to retain stemness due to the lack of paracrine factors. Our findings provide valuable knowledge for the development of effective therapeutic strategies targeting GICs at the invasion front.