The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.
The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.
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DOI：
10.1038/onc.2017.173
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发表时间：
2017-09-28
期刊：
影响因子：
8
通讯作者：
Watkins DN
中科院分区：
文献类型：
--
作者：
Szczepny A;Rogers S;Jayasekara WSN;Park K;McCloy RA;Cochrane CR;Ganju V;Cooper WA;Sage J;Peacock CD;Cain JE;Burgess A;Watkins DN
Hedgehog（Hh）信号调节细胞命运和自我更新的发展和癌症。典型的Hh信号传导由Hh配体与受体Patched（Ptch）结合介导，Patched（Ptch）进而通过Smoothened（Smo）激活Gli介导的转录，Smoothened（Smo）是用作癌症治疗剂的Hh通路抑制剂的分子靶标。小细胞肺癌（small cell lung cancer，SCLC）是一种常见的侵袭性恶性肿瘤，预后普遍较差.尽管临床前研究已经表明Hh抑制剂阻断SCLC细胞的自我更新能力，但缺乏活化途径突变使人们对这些观察结果的意义产生了怀疑。特别是，自分泌，配体依赖性Hh信号在SCLC中的存在一直存在争议。在有条件的TP 53; Rb 1突变小鼠模型的SCLC，我们现在证明了Hh配体Sonic Hedgehog（Shh）的SCLC的进展的要求。相反，我们表明，条件性Shh过表达激活典型的Hh信号在SCLC细胞，并显着加速肿瘤的进展。当与表达活化的、配体非依赖性Smo突变体的小鼠SCLC肿瘤相比时，过表达Shh的肿瘤表现出显著的染色体不稳定性和细胞周期蛋白B1的Smoothened非依赖性上调，细胞周期蛋白B1是Hh途径的一个假定的非典型臂。反过来，我们表明，细胞周期蛋白B1的过度表达诱导小鼠胚胎成纤维细胞缺乏Tp 53和Rb 1的染色体不稳定性。这些结果提供了强有力的支持，自分泌，配体依赖性模型的Hh信号在SCLC发病机制，并揭示了一种新的作用，非经典的Hh信号通过诱导染色体不稳定性。
Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.
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影响因子：
64.5
作者：
McFadden DG;Papagiannakopoulos T;Taylor-Weiner A;Stewart C;Carter SL;Cibulskis K;Bhutkar A;McKenna A;Dooley A;Vernon A;Sougnez C;Malstrom S;Heimann M;Park J;Chen F;Farago AF;Dayton T;Shefler E;Gabriel S;Getz G;Jacks T
通讯作者：
Jacks T
影响因子：
11.4
作者：
Barnes, EA;Kong, M;Donoghue, DJ
通讯作者：
Donoghue, DJ
DOI：
10.1073/pnas.1200094109
发表时间：
2012-06-26
影响因子：
11.1
作者：
Fombonne, Joanna;Bissey, Pierre-Antoine;Mehlen, Patrick
通讯作者：
Mehlen, Patrick
DOI：
10.1101/pdb.prot4706
发表时间：
2008-05-01
期刊：
CSH protocols
影响因子：
--
作者：
Nagy, Andras;Gertsenstein, Marina;Behringer, Richard
通讯作者：
Behringer, Richard
DOI：
10.1158/1541-7786.mcr-13-0554
发表时间：
2014-05
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Cui M;Augert A;Rongione M;Conkrite K;Parazzoli S;Nikitin AY;Ingolia N;MacPherson D
通讯作者：
MacPherson D