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

描述（由申请人提供）：胰腺导管腺癌的致死率是普遍的，即使是原发肿瘤较小并接受手术治疗的患者。因此，确定是否存在特定的分子改变有助于恶性前病变细胞的最终转化，无论是对早期发现还是对手术切除部位附近的前驱病变患者，都可能具有临床益处。由于肿瘤细胞密度低且肿瘤边缘不明确，在人类和小鼠组织中研究胰腺癌具有挑战性，因此我们开发了一种新的类器官细胞培养系统来扩增小鼠和人类原代正常、癌前和恶性胰腺导管细胞。这些类器官将使用转录组学、蛋白质组学和其他组学水平的方法进行全面的分子改变分析，以确定与胰腺癌早期进展相关的候选器官。使用常规和单细胞分析，将考虑对小鼠和人体组织的潜在治疗和/或诊断发展进行特定的分子改变。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疾病管理失败的原因可能是肿瘤局部再生或远处转移扩散。此外，如果癌前细胞有可能转变为恶性肿瘤

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.