Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution.
Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution.
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DOI：
10.3389/fonc.2022.929950
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发表时间：
2022
影响因子：
4.7
通讯作者：
Hwang, William L.
中科院分区：
文献类型：
--
作者：
Shiau, Carina;Su, Jennifer;Guo, Jimmy A.;Hong, Theodore S.;Wo, Jennifer Y.;Jagadeesh, Karthik A.;Hwang, William L.
胰腺导管腺癌是治疗难治性和致命性最高的恶性肿瘤之一。肿瘤微环境(TME)中内皮细胞(EC)谱系的多样性影响抗肿瘤治疗的疗效，而抗肿瘤治疗反过来又重塑EC的状态和分布。在这里，我们提出了在新辅助化疗、放射治疗和氯沙坦的背景下，PDAC TME中不同EC谱系的单细胞分辨框架。我们分析了来自37例原发PDAC标本的定制单核RNA-seq数据集(18例未经治疗，14例新辅助FOLFIRINOX+放化疗，5例新辅助FOLFIRINOX+放化疗+氯沙坦)。对15,185个EC图谱的单核转录组分析显示，两个状态程序(核糖体、循环)、四个谱系程序(毛细血管、动脉、静脉、淋巴)和一个程序与先前的签名没有明显重叠，但丰富了涉及血管生成、干细胞状态、对创伤和缺氧的反应以及内皮到间充质转化(反应性EndMT)的途径。对两个独立队列(n=269名患者)的批量转录组分析显示，淋巴和反应性EndMT谱系计划与较差的临床结果显著相关。虽然氯沙坦和质子疗法与淋巴管内皮细胞减少有关，但这些疗法也与反应性EndMT的增加有关。因此，开发EndMT抑制药物(例如，9tedanib)并将其纳入以氯沙坦和/或质子治疗为特色的新辅助放化疗方案，可能在耗尽淋巴和反应性EndMT人群和潜在改善患者预后方面最有效。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment refractory and lethal malignancies. The diversity of endothelial cell (EC) lineages in the tumor microenvironment (TME) impacts the efficacy of antineoplastic therapies, which in turn remodel EC states and distributions. Here, we present a single-cell resolution framework of diverse EC lineages in the PDAC TME in the context of neoadjuvant chemotherapy, radiotherapy, and losartan. We analyzed a custom single-nucleus RNA-seq dataset derived from 37 primary PDAC specimens (18 untreated, 14 neoadjuvant FOLFIRINOX + chemoradiotherapy, 5 neoadjuvant FOLFIRINOX + chemoradiotherapy + losartan). A single-nucleus transcriptome analysis of 15,185 EC profiles revealed two state programs (ribosomal, cycling), four lineage programs (capillary, arterial, venous, lymphatic), and one program that did not overlap significantly with prior signatures but was enriched in pathways involved in vasculogenesis, stem-like state, response to wounding and hypoxia, and endothelial-to-mesenchymal transition (reactive EndMT). A bulk transcriptome analysis of two independent cohorts (n = 269 patients) revealed that the lymphatic and reactive EndMT lineage programs were significantly associated with poor clinical outcomes. While losartan and proton therapy were associated with reduced lymphatic ECs, these therapies also correlated with an increase in reactive EndMT. Thus, the development and inclusion of EndMT-inhibiting drugs (e.g., nintedanib) to a neoadjuvant chemoradiotherapy regimen featuring losartan and/or proton therapy may be most effective in depleting both lymphatic and reactive EndMT populations and potentially improving patient outcomes.
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放疗后通过内皮到间质转变的肿瘤 - 脉管系统通过控制CD44V6（+）癌细胞和巨噬细胞极化。
影响因子：
16.6
作者：
Choi SH;Kim AR;Nam JK;Kim JM;Kim JY;Seo HR;Lee HJ;Cho J;Lee YJ
通讯作者：
Lee YJ
影响因子：
30.8
作者：
Chan-Seng-Yue, Michelle;Kim, Jaeseung C.;Notta, Faiyaz
通讯作者：
Notta, Faiyaz
影响因子：
4.6
作者：
Yamazaki, Tomoko;Young, Kristina H.
通讯作者：
Young, Kristina H.
DOI：
10.1158/1078-0432.ccr-17-2994
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Aung KL;Fischer SE;Denroche RE;Jang GH;Dodd A;Creighton S;Southwood B;Liang SB;Chadwick D;Zhang A;O'Kane GM;Albaba H;Moura S;Grant RC;Miller JK;Mbabaali F;Pasternack D;Lungu IM;Bartlett JMS;Ghai S;Lemire M;Holter S;Connor AA;Moffitt RA;Yeh JJ;Timms L;Krzyzanowski PM;Dhani N;Hedley D;Notta F;Wilson JM;Moore MJ;Gallinger S;Knox JJ
通讯作者：
Knox JJ
影响因子：
37.8
作者：
Schupp JC;Adams TS;Cosme C Jr;Raredon MSB;Yuan Y;Omote N;Poli S;Chioccioli M;Rose KA;Manning EP;Sauler M;DeIuliis G;Ahangari F;Neumark N;Habermann AC;Gutierrez AJ;Bui LT;Lafyatis R;Pierce RW;Meyer KB;Nawijn MC;Teichmann SA;Banovich NE;Kropski JA;Niklason LE;Pe'er D;Yan X;Homer RJ;Rosas IO;Kaminski N
通讯作者：
Kaminski N