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Novel imaging strategies to investigate 3D tumour invasion at the molecular level

在分子水平研究 3D 肿瘤侵袭的新颖成像策略

基本信息

批准号：
MR/T04067X/1
负责人：
Simon Poland
金额：
$ 124.48万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT04067X%2F1
关键词：
Novel imaging strategies investigate 3D

项目摘要

Cancer is the one of the major causes of deaths worldwide and despite our increased understanding and the development of more improved treatments, many advanced cancers are still incurable. The majority of these deaths are due to metastasis whereby through cascading events, cancer cells escape the primary tumour, acquiring cellular characteristics which enable them to colonise other parts of the body. Several underlying mechanisms of this process are not understood and require the development of new biological models which can mimic cellular interactions within these complex tumour ecosystems. Until now most of our understanding of the basic molecular principles of cancer have come from experimentation with single layer 2D cell culture models. Whilst inexpensive and easy to image, they are not representative of the way cells actually interact in an in vivo environment. 3D cell cultures (i.e. spheroids), have gained great significance in recent years as they can provide a much more realistic environment to simulate biological interactions. Unfortunately as the relative size, heterogeneity and hence complexity of these 3D cell cultures increases, it imposes severe limitations when imaging with any optically based technique. Local variations in refractive index induce optical aberrations and scattering, and coupled with absorption, lead to severe a degradation in optical resolution, as well as a loss in signal and contrast. The key objective of this fellowship is to develop novel optical imaging strategies which will enable for the first time, the complete interrogation of tumour derived spheroid models, to understand how cancer cells to dissociate from the primary tumour, evade immune surveillance and invade surrounding tissues. The imaging platform will be based on light sheet fluorescence microscopy (LSFM) to enable high-speed volumetric imaging capability. Building on previously conducted research at King's College London, the system will incorporate fluorescence lifetime imaging (FLIM) to allow functional information to be extracted, which will be instrumental in gaining an understanding of the molecular interactions taking place. Several aspects of the design will be considering including the incorporation of adaptive optical elements (i.e. spatial light modulator) to counteract aberrative effects in both the illumination and detection paths. Using this technology and working in close collaboration with a number of life scientists, tumour spheroid cultures will be constructed to closely imitate the tumour microenvironment (TME). Several aspects of this TME will be examined including (i) cell motility and migration of cancer cells and (ii) their effects on the structural modelling of the extra cellular matrix (iii) the role of immune cells in tumour progress.Analysis of this multivariate and multidimensional data represents a huge challenge and a number of conventional machine learning and deep learning techniques will be explored. The development of instrumentation to image, extract, and analyse functional information of large 3D cell culture models non-invasively, at high-speed and at high resolution is vital and will further improve our understanding of cellular complexities of interactions between cells and the Extracellular Matrix (ECM). This will serve to assist in the construction of more complex spheroid structures to mimic in vivo conditions and has enormous potential to aid in the development on specific anti-cancer therapies, revolutionising patient treatments and outcomes.

癌症是全世界死亡的主要原因之一，尽管我们对癌症的了解越来越多，并开发了更好的治疗方法，但许多晚期癌症仍然无法治愈。这些死亡中的大多数是由于转移，通过级联事件，癌细胞逃离原发性肿瘤，获得细胞特征，使它们能够在身体的其他部位定居。这一过程的几个基本机制尚不清楚，需要开发新的生物模型，可以模拟这些复杂的肿瘤生态系统中的细胞相互作用。到目前为止，我们对癌症基本分子原理的理解大多来自单层2D细胞培养模型的实验。虽然便宜且易于成像，但它们并不能代表细胞在体内环境中实际相互作用的方式。近年来，3D细胞培养物（即球状体）具有重要意义，因为它们可以提供更逼真的环境来模拟生物相互作用。不幸的是，随着这些3D细胞培养物的相对大小、异质性以及因此的复杂性的增加，当用任何基于光学的技术成像时，它施加了严重的限制。折射率的局部变化引起光学像差和散射，并且与吸收相结合，导致光学分辨率的严重退化，以及信号和对比度的损失。该奖学金的主要目标是开发新的光学成像策略，这将首次实现对肿瘤衍生球体模型的完整询问，以了解癌细胞如何从原发性肿瘤中解离，逃避免疫监视并侵入周围组织。成像平台将基于光片荧光显微镜（LSFM），以实现高速体积成像能力。在伦敦国王学院先前进行的研究的基础上，该系统将纳入荧光寿命成像（FLIM），以提取功能信息，这将有助于了解分子相互作用。设计的几个方面将被考虑，包括自适应光学元件（即空间光调制器）的结合，以抵消照明和检测路径中的像差效应。使用这项技术并与一些生命科学家密切合作，将构建肿瘤球体培养物，以密切模仿肿瘤微环境（TME）。该TME的几个方面将被检查，包括（i）癌细胞的细胞运动性和迁移，（ii）它们对细胞外基质结构建模的影响（iii）免疫细胞在肿瘤进展中的作用。分析这种多变量和多维数据是一个巨大的挑战，将探索一些传统的机器学习和深度学习技术。以非侵入性、高速和高分辨率对大型3D细胞培养模型的功能信息进行成像、提取和分析的仪器的开发至关重要，这将进一步提高我们对细胞与细胞外基质（ECM）之间相互作用的细胞复杂性的理解。这将有助于构建更复杂的球体结构以模拟体内条件，并具有巨大的潜力来帮助开发特定的抗癌疗法，彻底改变患者的治疗和结果。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small molecule PD-L1 inhibitor modulates expression of PD-L1 on the cell surface - a potential mechanism of blocking interaction with PD-1

小分子 PD-L1 抑制剂调节细胞表面 PD-L1 的表达——阻断与 PD-1 相互作用的潜在机制

DOI：
10.1016/s0959-8049(22)00989-3
发表时间：
2022
期刊：
European Journal of Cancer
影响因子：
8.4
作者：
Weitsman G
通讯作者：
Weitsman G

Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration.

DOI：
10.1038/s41467-021-25916-6
发表时间：
2021-09-28
期刊：
Nature communications
影响因子：
16.6
作者：
Law AL;Jalal S;Pallett T;Mosis F;Guni A;Brayford S;Yolland L;Marcotti S;Levitt JA;Poland SP;Rowe-Sampson M;Jandke A;Köchl R;Pula G;Ameer-Beg SM;Stramer BM;Krause M
通讯作者：
Krause M

Development of a high-speed line-scanning fluorescence lifetime imaging microscope for biological imaging.

开发用于生物成像的高速线扫描荧光寿命成像显微镜。