(PQA-4) Organoid Omics To Detect And Defeat Ductal Pancreatic Cancer

(PQA-4) 类器官组学检测和战胜导管胰腺癌

• 批准号: 9122093
• 负责人: David A Tuveson
• 金额: $ 56.05万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122093
• 关键词: Antibodies; Biological Models; Cancer Patient; Cell Culture System; Cell surface; Cells; Cellularity; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Diagnosis; Diagnostic; Disease; Disease Management; Distant; Ductal; Ductal Epithelial Cell; Early Diagnosis; Enzymes; Epitopes; Evaluation; Excision; Failure; Gene Expression; Goals; Health; Heterogeneity; Human; Implant; Investigation; Laboratories; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metastatic Adenocarcinoma; Molecular; Mus; Normal Cell; Operative Surgical Procedures; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Patient risk; Patients; Polysaccharides; Population; Premalignant; Primary Neoplasm; Proteomics; Recurrence; Resected; Site; Sorting - Cell Movement; Staging; Stromal Cells; Survival Rate; System; Techniques; Therapeutic; Time; Tissues; Work; biomarker panel; cancer cell; cell growth; cell type; design; diagnostic biomarker; genome editing; glycosylation; human tissue; in vivo; insight; knock-down; malignant state; mouse model; neoplastic; novel; novel therapeutic intervention; overexpression; potential biomarker; prevent; relapse risk; single cell analysis; study population; targeted agent; targeted treatment; therapeutic development; therapeutic target; tool; transcriptome sequencing; transcriptomics; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): The lethality of pancreatic ductal adenocarcinoma is universal, even in patients who present with small primary tumors and undergo surgery with curative intent. Therefore, determining whether there are specific molecular alterations contributing to the final transformation of pre- malignant cells, both for early detection and for patients with precursor lesions adjacent to their surgical resection site, may have clinical benefits. Since the investigation of pancreatic cancer in human and mouse tissues is challenging due to the low neoplastic cellularity and poorly defined tumor margins, we have developed a novel organoid cell culture system to expand primary mouse and human normal, pre-malignant and malignant pancreatic ductal cells. These organoids will be comprehensively analyzed for molecular alterations using transcriptomic, proteomic and other omics level approaches in order to identify candidates that correlate with the earliest stages of pancreatic cancer progression. Specific molecular alterations will be considered for potential therapeutic and/or diagnostic development in mouse and human tissues, using conventional and single cell analyses. Such findings will enable the identification of at risk patients, development of new therapeutic strategies, and provide new insights regarding how to prevent pancreatic cancer occurrence and recurrence. Significance The failure of disease management in pancreatic cancer patients following surgery is due to either local tumor regrowth or distant metastatic spread. In addition, if pre-malignant cells that are likely transform into a frank malignancy could be identified and treated before forming a tumor, many lives could be saved. In order to detect and treat pre-malignant cells that are poised to become tumorigenic in mice and patients, we will develop new organoid model systems and use these systems to better characterize and understand the transition from a pre- malignant disease state to invasive, metastatic adenocarcinoma.

描述(由申请人提供)：胰腺导管腺癌的致命性是普遍存在的，即使在存在小的原发肿瘤并为治疗目的而接受手术的患者中也是如此。因此，确定是否存在导致癌前细胞最终转化的特定分子改变，无论是为了早期发现还是对于手术切除部位附近有前驱病变的患者，都可能具有临床益处。由于肿瘤细胞密度低，肿瘤边缘模糊，人和小鼠胰腺癌的研究具有挑战性，我们开发了一种新的类器官细胞培养系统，用于原代培养小鼠和人类正常、癌前和恶性胰腺导管细胞。将使用转录、蛋白质组和其他组学水平的方法对这些有机化合物进行全面的分子变化分析，以确定与胰腺癌进展的早期阶段相关的候选基因。使用常规和单细胞分析，将考虑在小鼠和人类组织中进行潜在的治疗和/或诊断开发的特定分子变化。这些发现将有助于识别高危患者，开发新的治疗策略，并为如何预防胰腺癌的发生和复发提供新的见解。意义胰腺癌患者手术后的疾病处理失败是由于局部肿瘤再生长或远处转移扩散。此外，如果癌前细胞有可能转变为直白的恶性肿瘤， 在形成肿瘤之前进行识别和治疗，可以挽救许多人的生命。为了检测和治疗有可能在小鼠和患者身上致癌的癌前细胞，我们将开发新的器官模型系统，并使用这些系统来更好地表征和理解从癌前疾病状态到侵袭性、转移性腺癌的转变。