Multi-Modal analysis of composition and spatial architecture in human premalignant pancreatic lesions to enhance early detection.

胰腺癌仍然是一种总体预后很差的疾病。许多患者在出现症状时已经是癌症晚期。确诊5年后，每20名患者中只有1人能活下来。及时的调查、诊断和治疗对于任何治愈的可能性都是至关重要的，这需要早期手术和化疗相结合。通常，这些癌症起源于胰腺囊肿，尤其是导管内乳头状黏液肿瘤(IPMN)。CT和MRI扫描的广泛使用极大地增加了这些胰腺囊肿的发现。随后对这些包囊的监测消耗了大量的NHS资源。然而，在囊内发生癌症的风险通常很难确定。因此，胰腺囊肿的最佳治疗仍然是一个重要的临床难题。风险很高，因为胰腺癌的预后非常差，然而切除胰腺囊肿的胰腺手术平均有5%的死亡风险。因此，对于许多胰腺囊肿患者来说，确实存在不必要的检查和治疗的风险。为了帮助我们更好地选择患者进行治疗，迫切需要新的方法来提高我们在细胞水平上对癌前胰腺囊肿的理解。我们需要在这些囊肿发展成胰腺癌之前发现它们的变化，并确定为什么免疫系统无法阻止癌症的生长。在此之前，为了测量哪些基因被“激活”，肿瘤样本必须被消化，因此肿瘤和免疫细胞在“癌症战场”上的位置就失去了“地理位置”。该项目将采取三管齐下的方法来克服这一挑战。首先，我们将使用新的基因图谱技术研究手术切除的胰腺囊肿和癌症患者的组织。维持这一地理位置将有助于我们理解在包囊生长和进展过程中，在不同区域“开启”的基因之间的复杂关系。接下来，我们将研究“癌症免疫战场”，以帮助我们了解免疫细胞和胰腺癌细胞之间的位置、活动和相互关系，因为它们是从胰腺囊肿的衬里进化而来的。最后，从患者切除的胰腺囊肿中，我们将生长出肿瘤类器官。这些肿瘤的微型版本通过三维技术在实验室中生长，以更好地模拟原始肿瘤。使用这些囊性肿瘤的迷你版本，我们将使用基因编辑技术‘打开和关闭’重要基因，以识别那些将低风险囊性肿瘤转变为胰腺癌的特征。药物治疗也将进行试验，以减缓向癌症的转化。该项目将由一名外科实习生承担，他从临床培训中抽出时间专注于研究。他们将得到一个外科科学家团队的支持，以及一个由创造胰腺癌模型的世界领先科学家实验室组成的实验室。进一步的支持将由惠康信托桑格研究所提供，该研究所将协助种植有机化合物，以及一个由外科医生和病理学家组成的国际小组，这些医生和病理学家在管理意大利维罗纳的胰腺囊肿患者方面具有专业知识。这项工作有可能对这种几乎不治之症的管理产生影响。首先，通过发现新的标记物来帮助更早地发现胰腺癌，在更有可能治愈的阶段。其次，通过确定药物的靶点来减缓或防止胰腺癌在癌前囊中的发展。最终，我们希望这个项目将为每个患者提供个性化的治疗。帮助提高我们在扫描或血液测试中发现高风险成为胰腺癌的囊肿的能力；并避免对低风险囊肿的患者造成伤害。

Pancreatic cancer remains a disease with a poor overall prognosis. Many patients have advanced cancer by the time they develop symptoms. Only 1 in 20 patients will be alive 5 years after diagnosis. Prompt investigation, diagnosis and treatment are essential for any possibility of a cure, which requires a combination of early surgery and chemotherapy. Often these cancers develop from pancreatic cysts particularly an Intraductal Papillary Mucinous Neoplasms (IPMN). The widespread use of CT and MRI scans has dramatically increased discovery of these pancreatic cysts. Subsequent monitoring these cysts consumes a great amount of NHS resources. However, the risk of a cancer developing within a cyst is often very difficult to determine. Therefore, the optimal management of pancreatic cysts remains a significant clinical dilemma. The stakes are high, as pancreatic cancer has profoundly poor outcome, yet pancreatic surgery to remove the cyst carries with it on average a 5% risk of death. Therefore, a real risk of unnecessary investigation and treatment exists for many patients with pancreatic cysts. To help us better select patients for treatment, there is an urgent need for novel approaches to improve our understanding of pre-cancerous pancreatic cysts at a cellular level. We need to uncover changes in these cysts, before they develop into pancreatic cancer, and determine why the immune systems fails to stop the cancer growing. Previously, to measure which genes were 'switched-on', tumour samples had to be digested and so the 'geography' of where tumour and immune cells were positioned on the 'cancer battlefield' was lost. This project will have a three-pronged approach to overcome this challenge. Firstly, we will study tissue removed at surgery from patients with pancreatic cysts and cancer using new gene-mapping technology. Maintaining this geography will help us to understand the complex relationship between genes that are 'switched-on' in different regions of the cysts as they growth and progress. Next we will study the 'cancer immune battlefield', to help us understand the: Location, Activity, Inter-relationships between the immune cells and pancreatic cancer cells as they evolve from the lining of the pancreatic cysts. Finally, from pancreatic cysts resected from patients, we will grow tumour organoids. These miniaturised versions of a tumour are grown in the laboratory through three dimensional techniques to better mimic the original tumour. Using these mini-versions of the cyst tumours, we will 'switch on and off' important genes using gene editing techniques to identify those features that turn a low-risk cyst into a pancreatic cancer. Drugs treatments will also be trialled to slow the transformation into cancer. The project will be undertaken by a surgical trainee who has taken time out of his clinical training to focus on research. They will be supported by a team of surgeon scientists, and a world leading laboratory of scientists who create models of pancreatic cancer. Further support will be provided by the Wellcome Trust Sanger Institute who will assist in growing organoids and an international group of surgeons and pathologists with expertise in the management of patients with pancreatic cysts from Verona, Italy. This work has potential to impact the management of an almost incurable disease. Firstly, through the discovery of new markers to help with the detection of pancreatic cancer earlier, at a stage when cure is more likely. Secondly by identifying targets for drugs to slow or prevent pancreatic cancer developing in precancerous cysts.Ultimately, we hope this project will individualise treatment for each patient. Helping to improve our ability to detect on a scan or blood test those cysts at high-risk of becoming a pancreatic cancer; and avoid doing harm to patients with low-risk cysts.