Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma.
Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma.
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DOI：
10.1158/2767-9764.crc-22-0408
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发表时间：
2023-11-24
期刊：
影响因子：
--
通讯作者：
Onaitis, Mark W.
中科院分区：
文献类型：
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作者：
Chaudhary, Priyanka;Xu, Xia;Wang, Guangfang;Hoj, Jacob P.;Rampersad, Rishi R.;Asselin-Labat, Marie-Liesse;Ting, Stephanie;Kim, William;Tamayo, Pablo;Pendergast, Ann Marie;Onaitis, Mark W.
我们先前已经使用细胞系特异性诱导型Cre小鼠模型鉴定肺泡II型细胞为KrasG 12 D诱导的肺腺癌的起源细胞。使用功能获得和功能丧失的遗传模型，我们发现激活的Notch信号传导和低Sox 2水平决定了II型细胞在KrasG 12 D激活后增殖并进展为肺腺癌的能力。在这里，我们检查Kras激活后的II型细胞的表型，并发现共表达I型和II型标志物的细胞增殖的证据。三维类器官培养和移植研究确定这些双阳性细胞是高度可塑的，并且在体内引发肿瘤。RNA测序分析显示，这些双阳性细胞富含Ras/MAPK、EGFR和Notch途径。此外，这些细胞的增殖需要主动Notch信号传导，并受到遗传/化学Sox 2上调的抑制。我们的研究结果可能为靶向KRAS激活的肺腺癌提供新的治疗策略。在KRAS突变型肺腺癌中鉴定祖细胞样肿瘤起始细胞可能允许开发新的靶向治疗剂。
We have previously identified alveolar type II cell as the cell-of-origin of KrasG12D-induced lung adenocarcinoma using cell lineage–specific inducible Cre mouse models. Using gain-of-function and loss-of-function genetic models, we discovered that active Notch signaling and low Sox2 levels dictate the ability of type II cells to proliferate and progress into lung adenocarcinoma upon KrasG12D activation. Here, we examine the phenotype of type II cells after Kras activation and find evidence for proliferation of cells that coexpress type I and type II markers. Three-dimensional organoid culture and transplantation studies determine that these dual-positive cells are highly plastic and tumor initiating in vivo. RNA sequencing analysis reveals that these dual-positive cells are enriched in Ras/MAPK, EGFR, and Notch pathways. Furthermore, the proliferation of these cells requires active Notch signaling and is inhibited by genetic/chemical Sox2 upregulation. Our findings could provide new therapeutic strategies to target KRAS-activated lung adenocarcinomas. Identification of progenitor like tumor-initiating cells in KRAS-mutant lung adenocarcinoma may allow development of novel targeted therapeutics.
影响因子：
23.9
作者：
Curtis SJ;Sinkevicius KW;Li D;Lau AN;Roach RR;Zamponi R;Woolfenden AE;Kirsch DG;Wong KK;Kim CF
通讯作者：
Kim CF