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Characterising cancer-associated fibroblast heterogeneity in lung cancer: relating molecular phenotype to function

肺癌中癌症相关成纤维细胞异质性的特征：分子表型与功能的关系

基本信息

批准号：
MR/R001286/1
负责人：
Sara Waise
金额：
$ 18.98万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR001286%2F1
关键词：
Characterising cancer associated fibroblast heterogeneity

项目摘要

Lung cancer causes more deaths every year than any other cancer. Although there have recently been developments in the types of treatment available, fewer than 15% of patients with this disease survive longer than five years. In order to develop new treatments, it is critical to have an understanding of how lung tumour cancers develop and spread.The environment surrounding a developing tumour (known as the tumour microenvironment) is key to its growth and spread (metastasis). One cell type that plays an important role in these processes is the fibroblast. Fibroblasts are found in both normal and cancerous tissues (where they are referred to as cancer-associated fibroblasts, or CAFs). In many cancers, the presence of these cells is related to shorter survival. CAFs have a number of effects, which promote the invasion of tumour cells into surrounding tissues and their subsequent spread. However, there is a large degree of variation within the fibroblast population, and some types of fibroblast are able to impair tumour growth and metastasis. How these different types of fibroblasts arise is currently unknown. Targeting the fibroblast types that encourage cancer development, in combination with chemotherapy, is a potential future strategy for treating tumours. This project, led by world-renowned researchers and using cutting-edge techniques, aims to identify the different types of fibroblasts present in one of the types of lung cancer; non-small cell lung cancer (NSCLC). We also aim to determine whether the different fibroblast types have different effects on the behaviour of tumour and immune cells. Our initial goal is to group CAFs according to the genes they express, using non-small cell lung cancer samples from patients. We shall achieve this using a new technique called droplet barcoded sequencing ('Drop-Seq'): the University of Southampton is currently one of the few centres in the world with this technology. Drop-Seq captures individual cells in separate droplets. Each droplet is labelled with its own unique barcode, allowing identification of the genes expressed by each individual cell.We will then identify specific markers for each CAF subtype, and examine whether these can be used to predict patient survival or guide treatment. I shall carry out experiments examining the effects of different CAF types on both tumour cell invasion and the ability of immune cells to infiltrate tumours. Through our work exploring these subtypes, we hope to to identify new targets for the diagnosis and treatment of non-small cell lung cancer.This research is being performed at the University of Southampton, a UK centre of academic excellence, involving new laboratory techniques (Drop-Seq) that have been implemented locally. During this project, I shall acquire knowledge of molecular pathology and bioinformatic skills, for the handling and analysis of large amounts of data. These attributes will be invaluable in my future academic career and in my clinical training as a cellular pathologist. In the long term, I hope that this research will identify new targets for the diagnosis and treatment of non-small lung cancer, This would enable the development of new therapies, improving the survival of patients with non-small cell lung cancer, with the potential to apply these findings to other types of cancer in the future.

肺癌每年造成的死亡人数超过任何其他癌症。尽管最近在可用的治疗类型方面取得了进展，但只有不到15%的这种疾病患者存活时间超过5年。为了开发新的治疗方法，了解肺癌的发展和扩散是至关重要的。肿瘤周围的环境（称为肿瘤微环境）是肿瘤生长和扩散（转移）的关键。在这些过程中起重要作用的一种细胞类型是成纤维细胞。成纤维细胞存在于正常组织和癌变组织中（它们被称为癌症相关成纤维细胞，简称CAFs）。在许多癌症中，这些细胞的存在与较短的生存期有关。CAFs具有许多作用，可促进肿瘤细胞侵入周围组织并随后扩散。然而，在成纤维细胞群体中存在很大程度的差异，某些类型的成纤维细胞能够损害肿瘤的生长和转移。这些不同类型的成纤维细胞是如何产生的目前尚不清楚。靶向促进癌症发展的成纤维细胞类型，结合化疗，是治疗肿瘤的潜在未来策略。该项目由世界知名研究人员领导，采用尖端技术，旨在鉴定一种肺癌中存在的不同类型的成纤维细胞；非小细胞肺癌（NSCLC）。我们还旨在确定不同的成纤维细胞类型是否对肿瘤和免疫细胞的行为有不同的影响。我们最初的目标是使用来自患者的非小细胞肺癌样本，根据它们表达的基因对caf进行分组。我们将使用一种名为液滴条形码测序（Drop-Seq）的新技术来实现这一目标：南安普顿大学目前是世界上少数几个拥有这项技术的中心之一。Drop-Seq在单独的液滴中捕获单个细胞。每个液滴都有自己独特的条形码，可以识别每个细胞表达的基因。然后，我们将确定每种CAF亚型的特定标记物，并检查这些标记物是否可用于预测患者生存或指导治疗。我将进行实验，检查不同类型的CAF对肿瘤细胞侵袭和免疫细胞浸润肿瘤的能力的影响。通过我们对这些亚型的研究，我们希望找到诊断和治疗非小细胞肺癌的新靶点。这项研究是在南安普顿大学进行的，这是一个英国学术卓越中心，涉及新的实验室技术（Drop-Seq），已经在当地实施。在这个项目中，我需要掌握分子病理学知识和生物信息学技能，对大量数据进行处理和分析。这些特质在我未来的学术生涯和作为细胞病理学家的临床训练中将是无价的。从长远来看，我希望这项研究将为非小细胞肺癌的诊断和治疗确定新的靶点，这将使新疗法的发展，提高非小细胞肺癌患者的生存率，并有可能在未来将这些发现应用于其他类型的癌症。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Optimized Method to Isolate Human Fibroblasts from Tissue for ex vivo Analysis.

从组织中分离人成纤维细胞进行离体分析的优化方法。

DOI：
10.21769/bioprotoc.3440
发表时间：
2019
期刊：
Bio-protocol
影响因子：
0.8
作者：
Waise S
通讯作者：
Waise S

A non-linear optimisation method to extract summary statistics from Kaplan-Meier survival plots using the published P value.

DOI：
10.1186/s12874-020-01092-x
发表时间：
2020-10-30
期刊：
BMC medical research methodology
影响因子：
4
作者：
Irvine AF;Waise S;Green EW;Stuart B
通讯作者：
Stuart B

Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer.

DOI：
10.1038/s41467-023-35832-6
发表时间：
2023-01-31
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Hanley, Christopher J.;Waise, Sara;Ellis, Matthew J.;Lopez, Maria A.;Pun, Wai Y.;Taylor, Julian;Parker, Rachel;Kimbley, Lucy M.;Chee, Serena J.;Shaw, Emily C.;West, Jonathan;Alzetani, Aiman;Woo, Edwin;Ottensmeier, Christian H.;Rose-Zerilli, Matthew J. J.;Thomas, Gareth J.
通讯作者：
Thomas, Gareth J.

An optimised tissue disaggregation and data processing pipeline for characterising fibroblast phenotypes using single-cell RNA sequencing.

优化的组织分解和数据处理流程，用于使用单细胞 RNA 测序表征成纤维细胞表型。