Pancreatic cancer ascites xenograft-an expeditious model mirroring advanced therapeutic resistant disease
Pancreatic cancer ascites xenograft-an expeditious model mirroring advanced therapeutic resistant disease
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DOI：
10.18632/oncotarget.17253
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发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Berger, Raanan
中科院分区：
文献类型：
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作者：
Golan, Talia;Stossel, Chani;Berger, Raanan
胰腺导管腺癌的治疗选择有限。目前迫切需要开发合适的临床前模型来重现转移性疾病，这是目前最常见的临床情况。高达20-30%的胰腺癌患者发生腹水积聚;这种环境代表了转移性腹膜扩散的高度细胞研究资源。在这项研究中，我们利用胰腺腹水/胸腔积液癌细胞建立患者来源的异种移植物。从12个独立病例中建立腹水/胸腔积液患者来源的异种移植物。异种移植物在裸鼠中连续传代，并建立了组织生物标本库。新出现的肿瘤的组织学表现为低至中等分化的腺性和粘液性肿瘤，反映了原发性胰腺癌肿瘤的形态。六个患者来源的异种移植物样品的全基因组测序表明常见的突变和结构变异与原发性胰腺癌中报道的相似。异种移植瘤被分离成单细胞，体外药物敏感性筛选试验显示化疗耐药性，与患者临床情况相关，因此作为临床相关转化研究的平台，因此，建立这种新的腹水/胸腔积液患者来源的异种移植瘤模型，具有广泛的组织病理学和基因组特征，为晚期侵袭性胰腺癌的研究提供了机会。转移性疾病的表征和对治疗剂的抗性机制可能导致新的药物组合的开发。
Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation.Ascites accumulation occurs in up to 20-30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts. Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research.Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations.