Identifying and manipulating molecular mechanisms controlling cancer stem cell metastatic potential in a human oral cancer model.

识别和操纵控制人类口腔癌模型中癌症干细胞转移潜力的分子机制。

• 批准号: MR/V009494/1
• 负责人: Adrian Biddle
• 金额: $ 70.4万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FV009494%2F1
• 关键词: Identifying; manipulating; molecular; mechanisms; controlling

Tumour metastasis, which seeds secondary tumours in distant organs, causes the majority of cancer deaths. Cancer stem cells drive tumour metastasis. To do this, they undergo epithelial-mesenchymal transition (EMT) to adopt a migratory mesenchymal phenotype that can disseminate from the primary tumour and migrate to secondary sites. Upon reaching secondary sites, they then undergo mesenchymal-epithelial transition (MET) to re-gain a proliferative epithelial phenotype that can form a secondary tumour. This process is known as the metastatic cascade. For this to occur, epithelial cancer stem cells within the primary tumour must possess the ability to undergo EMT into a mesenchymal phenotype that in turn retains the ability to undergo MET at a secondary site - this ability to switch phenotype is termed 'plasticity'. The ability to therapeutically control the plasticity of epithelial cancer stem cells to prevent initiation of the metastatic cascade would stop tumour metastasis at its root. We hypothesise that there is variation within the epithelial cancer stem cell population in the primary tumour - only some of these cancer stem cells possess the plasticity required to initiate the metastatic cascade. We further hypothesise that it is possible to therapeutically manipulate the plasticity of epithelial cancer stem cells, and thereby prevent metastatic transitions. We propose to test these hypotheses in a human oral cancer model treated with the well-characterised EMT-inducer TGFbeta. New single cell approaches are a powerful tool for dissecting variation within cell populations, and provide a means to probe the existence of discrete epithelial cancer stem cell sub-populations with differing responses to TGFbeta. We will use single cell RNAseq to identify distinct epithelial cancer stem cell sub-populations and infer the ability of these sub-populations to undergo EMT into a mesenchymal phenotype that in turn retains the ability to undergo MET. We will use this information to identify candidate molecular pathways controlling these cancer stem cell sub-populations, and inactivate these pathways using a CRISPR screening methodology combined with single cell RNAseq in order to determine molecular targets whose inactivation can prevent initiation of the metastatic cascade. In selecting targets, we will focus on druggable nodes within key pathways. We will then test the importance of these targets in metastasis using human pathological specimens, and whether inactivating these targets can prevent metastasis in new engineered metastasis models that we have developed in our lab. Oral cancer is one of the top ten cancers worldwide, with over 300,000 cases annually, and incidence is increasing both worldwide and in the UK (in the UK, incidence has increased by 23% over the past decade). Oral cancer is a deadly disease with frequent metastatic spread, which is the single most important predictor of poor outcome. This research project will generate important knowledge of the molecular pathways controlling metastasis in oral cancer and, given the central role of EMT in metastasis, this may be generalizable to other tumour types. Targets emerging from this study will be taken forward for the development of new targeted therapies to prevent metastasis.

大多数癌症死亡是由肿瘤转移引起的，肿瘤转移会在远处器官产生继发性肿瘤。肿瘤干细胞驱动肿瘤转移。为了做到这一点，它们经历上皮-间质转化（EMT），采用一种迁移的间质表型，这种表型可以从原发肿瘤传播并迁移到继发部位。在到达继发部位后，它们经历间充质上皮转化（MET），重新获得可形成继发肿瘤的增生性上皮表型。这个过程被称为转移级联。为了实现这一点，原发肿瘤内的上皮性癌症干细胞必须具备将EMT转化为间充质表型的能力，而这种能力反过来又保留了在继发部位接受MET的能力——这种转换表型的能力被称为“可塑性”。从治疗上控制上皮性癌症干细胞的可塑性以防止转移级联的启动的能力将从根本上阻止肿瘤转移。我们假设在原发肿瘤的上皮性癌症干细胞群中存在变异——只有一些癌症干细胞具有启动转移级联所需的可塑性。我们进一步假设，有可能在治疗上操纵上皮癌干细胞的可塑性，从而防止转移转移。我们建议用表征良好的emt诱导剂tgf β治疗的人类口腔癌模型来测试这些假设。新的单细胞方法是解剖细胞群内变异的有力工具，并提供了一种方法来探测对tgf - β有不同反应的离散上皮癌干细胞亚群的存在。我们将使用单细胞RNAseq来鉴定不同的上皮性癌症干细胞亚群，并推断这些亚群经历EMT的能力，并将其转化为间充质表型，从而保留经历MET的能力。我们将利用这些信息来确定控制这些癌症干细胞亚群的候选分子途径，并使用CRISPR筛选方法结合单细胞RNAseq灭活这些途径，以确定其灭活可以阻止转移级联启动的分子靶点。在选择靶点时，我们将重点关注关键通路内的可用药节点。然后，我们将使用人类病理标本测试这些靶点在转移中的重要性，以及在我们实验室开发的新的工程转移模型中，灭活这些靶点是否可以防止转移。口腔癌是全球十大癌症之一，每年有超过30万例病例，全球和英国的发病率都在增加（在英国，发病率在过去十年中增加了23%）。口腔癌是一种致命的疾病，具有频繁的转移性扩散，这是预后不良的最重要的预测因素。该研究项目将对口腔癌转移控制的分子途径产生重要的认识，并且鉴于EMT在转移中的核心作用，这可能推广到其他类型的肿瘤。从这项研究中出现的靶点将被用于开发新的靶向治疗来防止转移。

项目成果

In vitro cancer models as an approach to identify targetable developmental phenotypes in cancer stem cells.

• DOI: 10.1007/s44164-023-00051-2
• 发表时间: 2023
• 期刊: In vitro models

CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells.

• DOI: 10.1126/sciadv.adi0244
• 发表时间: 2023-10-20
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Samain, Remi;Maiques, Oscar;Monger, Joanne;Lam, Hoyin;Candido, Juliana;George, Samantha;Ferrari, Nicola;Kohihammer, Leonie;Lunetto, Sophia;Varela, Adrian;Orgaz, Jose L.;Vilardell, Felip;Olsina, Jorge Juan;Matias-Guiu, Xavier;Sarker, Debashis;Biddle, Adrian;Balkwill, Frances R.;Eyles, Jim;Wilkinson, Robert W.;Kocher, Hemant M.;Calvo, Fernando;Wells, Claire M.;Sanz-Moreno, Victoria
• 通讯作者: Sanz-Moreno, Victoria

Organ-on-a-Chip Technologies Network special issue editorial

芯片器官技术网络特刊社论

• DOI: 10.1007/s44164-022-00039-4
• 发表时间: 2022
• 期刊: In vitro models
• 作者: Biddle A

Development of an in vitro microfluidic model to study the role of microenvironmental cells in oral cancer metastasis

开发体外微流体模型来研究微环境细胞在口腔癌转移中的作用

• DOI: 10.12688/f1000research.131810.1
• 发表时间: 2023
• 期刊: F1000Research
• 作者: Scemama A