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

对人类癌前胰腺病变的成分和空间结构进行多模态分析，以增强早期检测。

• 批准号: MR/V029711/1
• 负责人: Andrew Cameron
• 金额: $ 29.04万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV029711%2F1
• 关键词: Multi; Modal; analysis; composition; spatial

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.

胰腺癌仍然是一种总体预后较差的疾病。许多患者在出现症状时已是晚期癌症。诊断后 5 年内，只有十分之一的患者能够存活。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的结合。这些癌症通常由胰腺囊肿特别是导管内乳头状粘液性肿瘤（IPMN）发展而来。 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率。随后监测这些囊肿会消耗大量 NHS 资源。然而，囊肿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，因为胰腺癌的预后极差，而切除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接受治疗的患者，迫切需要新的方法来提高我们对细胞水平上的癌前胰腺囊肿的了解。我们需要在这些囊肿发展成胰腺癌之前发现它们的变化，并确定免疫系统无法阻止癌症生长的原因。以前，为了测量哪些基因被“打开”，肿瘤样本必须被消化，因此肿瘤和免疫细胞在“癌症战场”上所处的“地理位置”就丢失了。该项目将采用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在手术中从胰腺囊肿和癌症患者身上切除的组织。维持这种地理分布将有助于我们理解随着囊肿生长和进展而在囊肿不同区域“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从胰腺囊肿内壁演化时的位置、活性、相互关系。最后，我们将从患者身上切除的胰腺囊肿中培养出肿瘤类器官。这些微型肿瘤是通过三维技术在实验室中生长的，以更好地模仿原始肿瘤。使用这些囊肿肿瘤的迷你版本，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肿转变为胰腺癌的特征。还将尝试药物治疗以减缓癌症的转变。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。他们将得到外科医生科学家团队和创建胰腺癌模型的世界领先科学家实验室的支持。威康信托桑格研究所（Wellcome Trust Sanger Institute）将提供进一步的支持，该研究所将协助培养类器官，以及来自意大利维罗纳的一个由外科医生和病理学家组成的国际小组，他们在治疗胰腺囊肿患者方面拥有专业知识。这项工作有可能影响一种几乎无法治愈的疾病的治疗。首先，通过发现新的标记物来帮助在更有可能治愈的阶段更早地检测胰腺癌。其次，通过确定药物靶标来减缓或预防癌前囊肿中胰腺癌的发展。最终，我们希望该项目能为每位患者提供个体化治疗。帮助提高我们通过扫描或血液测试检测那些有可能成为胰腺癌的高风险囊肿的能力；并避免伤害低风险囊肿患者。

项目成果

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data.

• DOI: 10.1158/1078-0432.ccr-22-1102
• 发表时间: 2022-09-15
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Fisher, Natalie C.;Byrne, Ryan M.;Leslie, Holly;Wood, Colin;Legrini, Assya;Cameron, Andrew J.;Ahmaderaghi, Baharak;Corry, Shania M.;Malla, Sudhir B.;Amirkhah, Raheleh;McCooey, Aoife J.;Rogan, Emily;Redmond, Keara L.;Sakhnevych, Svetlana;Domingo, Enric;Jackson, James;Loughrey, Maurice B.;Leedham, Simon;Maughan, Tim;Lawler, Mark;Sansom, Owen J.;Lamrock, Felicity;Koelzer, Viktor H.;Jamieson, Nigel B.;Dunne, Philip D.
• 通讯作者: Dunne, Philip D.

Spatially Resolved Transcriptomics Deconvolutes Histological Prognostic Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases

• DOI: 10.1101/2022.09.21.508569
• 发表时间: 2022-09
• 期刊: bioRxiv
• 作者: C. Wood;K. Pennel;H. Leslie;A. Legrini;Andrew J Cameron;Lydia Melissourgou-Syka;J. Quinn;H. V. van Wyk;Jennifer Hay;A. Roseweir;C. Nixon;C. Roxburgh;D. McMillan;A. Biankin;O. Sansom;P. Horgan;J. Edwards;C. Steele;N. Jamieson

Risk of Recurrence after Surgical Resection for Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasia (IPMN) with Patterns of Distribution and Treatment An International, Multicentre, Observational Study

导管内乳头状粘液性肿瘤 (IPMN) 引起的腺癌手术切除后的复发风险及其分布和治疗模式 一项国际多中心观察性研究

• DOI: 10.1097/sla.0000000000006144
• 发表时间: 2023
• 期刊: Annals of Surgery
• 影响因子: 9
• 作者: Lucocq J