Falletta Paola, Sanchez-Del-Campo Luis, Chauhan Jagat, Effern Maike, Kenyon Amy, Kershaw Christopher J, Siddaway Robert, Lisle Richard, Freter Rasmus, Daniels Matthew J, Lu Xin, Tüting Thomas, Middleton Mark, Buffa Francesca M, Willis Anne E, Pavitt Graham, Ronai Ze'ev A, Sauka-Spengler Tatjana, Hölzel Michael, Goding Colin R
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
Department of Clinical Chemistry and Clinical Pharmacology, Unit for RNA Biology, University Hospital of Bonn, D-53127 Bonn, Germany.
Genes Dev. 2017 Jan 1;31(1):18-33. doi: 10.1101/gad.290940.116. Epub 2017 Jan 17.
The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.
肿瘤内微环境产生表型不同但可相互转化的恶性细胞亚群，这些亚群促进转移扩散和治疗抗性。不同的微环境线索是否通过共同机制赋予侵袭性或治疗抗性表型尚不清楚。在黑色素瘤中，谱系存活癌基因小眼相关转录因子（MITF）的低表达与侵袭、衰老和耐药性相关。然而，MITF在体内如何被抑制以及肿瘤中的MITF低表达细胞如何逃脱衰老，目前了解甚少。在这里，我们表明，包括炎症介导的对过继性T细胞免疫疗法的抗性在内的微环境线索，在翻译起始因子eIF2B受到抑制时，通过ATF4转录抑制MITF。ATF4是整合应激反应的关键转录介质，它还激活AXL并抑制衰老，从而赋予在人类肿瘤中观察到的MITF低/AXL高耐药表型。然而，出乎意料的是，在没有翻译重编程的情况下，ATF4高/MITF低状态不足以驱动侵袭。重要的是，翻译重编程显著增强肿瘤发生，并与先前无法解释的与抗PD-1免疫疗法抗性相关的基因表达程序有关。由于我们表明抑制eIF2B也会驱动神经嵴迁移和酵母侵袭性，我们的结果表明，翻译重编程是一种进化上保守的饥饿反应，已被黑色素瘤中的微环境应激信号劫持，以驱动表型可塑性和侵袭，并决定治疗结果。
