LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population during Temozolomide Therapy in Glioblastoma.
LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population during Temozolomide Therapy in Glioblastoma.
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DOI：
10.3390/cancers12123505
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发表时间：
2020-11-25
期刊：
影响因子：
5.2
通讯作者：
Ahmed AU
中科院分区：
文献类型：
--
作者：
Baisiwala S;Hall RR 3rd;Saathoff MR;M Shireman J;Park C;Budhiraja S;Goel C;Warnke L;Hardiman C;Wang JY;McCortney K;Horbinski CM;Ahmed AU
胶质母细胞瘤是最常见的成人恶性脑肿瘤。它是一种侵袭性肿瘤，即使在手术切除和基于替莫唑胺的化疗和放疗后也会复发。我们的目标是了解替莫唑胺改变了哪些基因，以及这些基因如何导致肿瘤复发。我们的工作表明，改变的基因之一是LNX1，它增加了Notch1的表达，Notch1是一种对胶质母细胞瘤进展很重要的基因。我们进一步表明，LNX1和Notch1的升高导致肿瘤干细胞群的增加，这是一种被认为有助于传播更具侵袭性肿瘤的细胞亚群。最后，我们发现，LNX1表达的强制减少导致植入胶质母细胞瘤的动物的存活率增加。总之，这些结果表明，LNX1可能是一种新的治疗靶点，可以调节Notch1活性和干细胞群，可能导致患者生存率增加。胶质母细胞瘤（GBM）是成人中最常见的原发性脑恶性肿瘤，复发率为100%，中位生存期为21个月。我们的实验室和其他实验室已经表明，GBM含有胶质瘤干细胞（GSC）的亚群，这些干细胞在化疗期间扩增，并可能导致GBM的治疗抗性和复发。为了研究这种扩增背后的机制，我们将基因集表达分析（GSEA）应用于患者来源的异种移植（PDX）细胞，以响应替莫唑胺（TMZ），这是最常用的针对GBM的化疗。结果显示癌症干细胞和细胞周期途径的显著富集（错误发现率（FDR）< 0.25）。Numb蛋白1（LNX1）的配体（一种已知的通过靶向负调节子Numb的Notch信号传导调节子）在TMZ治疗后强烈上调（p < 0.0001），并且与GBM患者的存活率呈负相关。在多个PDX系中，TMZ治疗后LNX1也上调，同时伴有Numb下调和细胞内Notch1（NICD）上调。LNX1的过表达导致Notch1信号传导激活和GSC群体增加。相反，敲低LNX1逆转了这些变化，导致NICD的显著下调，TMZ治疗后干性减少，并导致小鼠模型中的中位生存期延长。基于此，我们提出，在抗GBM化疗期间，LNX1调节的Notch1信号传导促进了干性并有助于治疗抗性。
Glioblastoma is the most common adult malignant brain tumor. It is an aggressive tumor that returns even after surgical removal and temozolomide-based chemotherapy and radiation. Our goal was to understand what genes are altered by temozolomide and how those genes may contribute to tumor return. Our work shows that one of the genes altered is LNX1, which increases the expression of Notch1, a gene important for glioblastoma progression. We further showed that the elevation of LNX1 and Notch1 results in an increase in the tumor stem cell population, a subpopulation of cells thought to help propagate a more aggressive tumor. Finally, we showed that forced reduction in LNX1 expression results in increased survival of animals implanted with glioblastoma. Together, these results suggest that LNX1 may be a novel therapeutic target that would allow modulation of Notch1 activity and the stem cell population, potentially resulting in increased patient survival. Glioblastoma (GBM) is the most common primary brain malignancy in adults, with a 100% recurrence rate and 21-month median survival. Our lab and others have shown that GBM contains a subpopulation of glioma stem cells (GSCs) that expand during chemotherapy and may contribute to therapeutic resistance and recurrence in GBM. To investigate the mechanism behind this expansion, we applied gene set expression analysis (GSEA) to patient-derived xenograft (PDX) cells in response to temozolomide (TMZ), the most commonly used chemotherapy against GBM. Results showed significant enrichment of cancer stem cell and cell cycle pathways (False Discovery Rate (FDR) < 0.25). The ligand of numb protein 1 (LNX1), a known regulator of Notch signaling by targeting negative regulator Numb, is strongly upregulated after TMZ therapy (p < 0.0001) and is negatively correlated with survival of GBM patients. LNX1 is also upregulated after TMZ therapy in multiple PDX lines with concomitant downregulations in Numb and upregulations in intracellular Notch1 (NICD). Overexpression of LNX1 results in Notch1 signaling activation and increased GSC populations. In contrast, knocking down LNX1 reverses these changes, causing a significant downregulation of NICD, reduction in stemness after TMZ therapy, and resulting in more prolonged median survival in a mouse model. Based on this, we propose that during anti-GBM chemotherapy, LNX1-regulated Notch1 signaling promotes stemness and contributes to therapeutic resistance.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.7
作者：
Lee G;Auffinger B;Guo D;Hasan T;Deheeger M;Tobias AL;Kim JY;Atashi F;Zhang L;Lesniak MS;James CD;Ahmed AU
通讯作者：
Ahmed AU
影响因子：
11.2
作者：
Chen G;Kong J;Tucker-Burden C;Anand M;Rong Y;Rahman F;Moreno CS;Van Meir EG;Hadjipanayis CG;Brat DJ
通讯作者：
Brat DJ
胶质母细胞瘤的临床分层基于视网膜细胞瘤抑制蛋白（RB1）的变化以及与胸部亚型的关联。
DOI：
10.1097/nen.0b013e31823fe8f1
发表时间：
2012-01
影响因子：
3.2
作者：
Goldhoff P;Clarke J;Smirnov I;Berger MS;Prados MD;James CD;Perry A;Phillips JJ
通讯作者：
Phillips JJ
影响因子：
9
作者：
通讯作者：
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