Genovese Giannicola, Carugo Alessandro, Tepper James, Robinson Frederick Scott, Li Liren, Svelto Maria, Nezi Luigi, Corti Denise, Minelli Rosalba, Pettazzoni Piergiorgio, Gutschner Tony, Wu Chia-Chin, Seth Sahil, Akdemir Kadir Caner, Leo Elisabetta, Amin Samirkumar, Molin Marco Dal, Ying Haoqiang, Kwong Lawrence N, Colla Simona, Takahashi Koichi, Ghosh Papia, Giuliani Virginia, Muller Florian, Dey Prasenjit, Jiang Shan, Garvey Jill, Liu Chang-Gong, Zhang Jianhua, Heffernan Timothy P, Toniatti Carlo, Fleming Jason B, Goggins Michael G, Wood Laura D, Sgambato Alessandro, Agaimy Abbas, Maitra Anirban, Roberts Charles W M, Wang Huamin, Viale Andrea, DePinho Ronald A, Draetta Giulio F, Chin Lynda
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nature. 2017 Feb 16;542(7641):362-366. doi: 10.1038/nature21064. Epub 2017 Feb 8.
Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.
恶性肿瘤会随着致癌信号的变化而演变。癌细胞对进化压力的可塑性是肿瘤进展和治疗耐药性发展的基础。在此，我们在胰腺导管腺癌（PDAC）的条件性致癌Kras小鼠模型中确定了癌细胞可塑性的分子和细胞机制，PDAC是一种具有显著表型多样性和形态异质性的恶性肿瘤。在该模型中，致癌Kras信号的随机消失以及Kras非依赖性逃逸群体（获得致癌特性的细胞）的出现与去分化和侵袭性生物学行为相关。对Kras非依赖性逃逸细胞的转录组学和功能分析揭示了存在由Smarcb1-Myc网络驱动的间充质重编程以及对MAPK信号的独立性。一种允许对细胞命运进行时间限制扰动的PDAC体细胞镶嵌模型表明，Smarcb1的缺失会激活Myc网络，驱动一种合成代谢转换，增加蛋白质代谢并适应性激活内质网应激诱导的生存途径。蛋白质周转率的增加使间充质亚群对细胞蛋白质稳态机制以及内质网应激反应途径的IRE1-α-MKK4臂的药理学和基因扰动高度敏感。具体而言，损害未折叠蛋白反应的联合治疗方案可阻断小鼠和患者来源的PDAC模型中侵袭性间充质亚群的出现。这些分子和生物学见解为靶向PDAC侵袭性间充质特征的潜在治疗策略提供了依据。
