Spatiotemporal analysis of induced neural stem cell therapy to overcome advanced glioblastoma recurrence.
Spatiotemporal analysis of induced neural stem cell therapy to overcome advanced glioblastoma recurrence.
复制标题
诱导神经干细胞治疗克服晚期胶质母细胞瘤复发的时空分析。
DOI：
10.1016/j.omto.2022.06.004
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发表时间：
2022-09-15
期刊：
影响因子：
--
通讯作者：
Hingtgen, Shawn
中科院分区：
文献类型：
--
作者：
Satterlee, Andrew B.;Dunn, Denise E.;Valdivia, Alain;Malawsky, Daniel;Buckley, Andrew;Gershon, Timothy;Floyd, Scott;Hingtgen, Shawn
基因工程神经干细胞（NSC）是治疗高度侵袭性脑癌胶质母细胞瘤（GBM）的一种有前景的疗法；然而，治疗持久性仍然是一个重大挑战。我们试图确定在用人皮肤源性诱导 NSC 释放促凋亡剂 TRAIL (iNSC-TRAIL) 治疗期间有助于 GBM 动态适应的事件，并制定将最初的肿瘤杀死转化为持续的 GBM 抑制的策略。治疗前、治疗期间和治疗后的体内和离体分析显示，随着肿瘤适应治疗，肿瘤转录组和空间分布发生显着变化。为了解决这个问题，我们设计了 iNSC 递送策略，增加了时空 TRAIL 覆盖范围，并显着减少了整个大脑的 GBM 体积，将肿瘤负荷减少了 100 倍（根据活体外脑切片的量化结果）。不同策略对实体瘤和侵袭性肿瘤的治疗持久性和中位生存期的不同影响为优化 iNSC 治疗提供了重要指导。使用当前的治疗策略几乎不可能预防晚期胶质母细胞瘤的复发。体内和离体肿瘤模型的耦合使我们能够更好地了解诱导神经干细胞治疗的时空疗效，并通过最大限度地提高功能剂量重叠和整体治疗覆盖范围来改善结果。
Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM); however, treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaptation of GBM during treatment with human skin-derived induced NSCs releasing the pro-apoptotic agent TRAIL (iNSC-TRAIL) and develop strategies that convert initial tumor kill into sustained GBM suppression. In vivo and ex vivo analysis before, during, and after treatment revealed significant shifts in tumor transcriptome and spatial distribution as the tumors adapted to treatment. To address this, we designed iNSC delivery strategies that increased spatiotemporal TRAIL coverage and significantly decreased GBM volume throughout the brain, reducing tumor burden 100-fold as quantified in live ex vivo brain slices. The varying impact of different strategies on treatment durability and median survival of both solid and invasive tumors provides important guidance for optimizing iNSC therapy. Recurrence of advanced glioblastoma is almost impossible to prevent using current therapeutic strategies. Coupling in vivo and ex vivo tumor models allows us to better understand the spatiotemporal efficacy of induced neural stem cell therapy and improve outcomes by maximizing functional dose overlap and overall therapeutic coverage.
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影响因子：
5.3
作者：
Shah, Khalid;Hingtgen, Shawn;Weissleder, Ralph
通讯作者：
Weissleder, Ralph
影响因子：
12.4
作者：
Buckley, Andrew;Hagler, Shaye B.;Hingtgen, Shawn D.
通讯作者：
Hingtgen, Shawn D.
影响因子：
5.7
作者：
Hingtgen S;Ren X;Terwilliger E;Classon M;Weissleder R;Shah K
通讯作者：
Shah K
影响因子：
8.8
作者：
Rheinbay E;Suvà ML;Gillespie SM;Wakimoto H;Patel AP;Shahid M;Oksuz O;Rabkin SD;Martuza RL;Rivera MN;Louis DN;Kasif S;Chi AS;Bernstein BE
通讯作者：
Bernstein BE
影响因子：
64.5
作者：
Suvà ML;Rheinbay E;Gillespie SM;Patel AP;Wakimoto H;Rabkin SD;Riggi N;Chi AS;Cahill DP;Nahed BV;Curry WT;Martuza RL;Rivera MN;Rossetti N;Kasif S;Beik S;Kadri S;Tirosh I;Wortman I;Shalek AK;Rozenblatt-Rosen O;Regev A;Louis DN;Bernstein BE
通讯作者：
Bernstein BE