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

描述（由申请方提供）：胰腺导管腺癌的致死性是普遍的，即使在原发性小肿瘤并接受手术治疗的患者中也是如此。因此，确定是否存在有助于恶变前细胞的最终转化的特定分子改变，对于早期检测和具有邻近其手术切除部位的前驱病变的患者，可能具有临床益处。由于人和小鼠组织中胰腺癌的研究由于低肿瘤细胞性和不明确的肿瘤边缘而具有挑战性，我们开发了一种新的类器官细胞培养系统来扩增原代小鼠和人正常、癌前和恶性胰腺导管细胞。将使用转录组学、蛋白质组学和其他组学水平的方法对这些类器官的分子改变进行全面分析，以确定与胰腺癌进展的最早阶段相关的候选者。使用常规和单细胞分析，将考虑特定分子改变用于小鼠和人组织中的潜在治疗和/或诊断开发。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。胰腺癌患者手术后疾病管理的失败是由于局部肿瘤再生长或远处转移扩散。此外，如果有可能转化为恶性肿瘤的癌前细胞， 如果在形成肿瘤之前就能被发现并得到治疗，许多生命就可以被挽救。为了检测和治疗在小鼠和患者中准备成为致瘤性的癌前细胞，我们将开发新的类器官模型系统，并使用这些系统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。

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.