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.

肿瘤转移在遥远的器官中种子染色体染色，导致大多数癌症死亡。癌症干细胞驱动肿瘤转移。为此，他们经历了上皮 - 间质转变（EMT），以采用可以从原发性肿瘤中传播并迁移到次要部位的迁移性间充质表型。到达次要位点后，他们会经历间质上皮过渡（MET），以重新获得一种可以形成次级肿瘤的增殖上皮表型。这个过程称为转移级联。为此，原发性肿瘤内的上皮癌干细胞必须具有将EMT经历到间充质表型中的能力，进而保留在次要部位进行MET的能力 - 这种切换表型的能力称为“可塑性”。治疗能力控制上皮癌干细胞的可塑性防止转移性级联反应的能力会阻止肿瘤转移的根。我们假设原发性肿瘤的上皮癌干细胞种群存在变化 - 只有其中一些癌细胞具有启动转移性级联反应所需的可塑性。我们进一步假设可以治疗性地操纵上皮癌干细胞的可塑性，从而防止转移过渡。我们建议在用良好的EMT诱导剂TGFBETA治疗的人口腔癌模型中检验这些假设。新的单细胞方法是剖析细胞种群中变异的强大工具，并提供了一种探测离散上皮癌干细胞亚群的存在，对TGFBETA的反应不同。我们将使用单细胞RNASEQ识别不同的上皮癌干细胞亚种群，并推断这些亚群将EMT经历EMT的能力又可以依次保留了经历MET的能力。我们将使用此信息来识别控制这些癌症干细胞亚群的候选分子途径，并使用CRISPR筛选方法与单细胞RNASEQ结合使用CRISPR筛选方法使这些途径失活，以确定灭活可以防止转移级联反应的分子靶标。在选择目标时，我们将专注于关键途径中的可毒节点。然后，我们将使用人类病理标本来测试这些靶标在转移中的重要性，以及使这些靶标失活是否可以防止我们在实验室中开发的新工程转移模型中的转移。口腔癌是全球十大癌症之一，每年有30万例病例，并且在全球范围内和英国的发病率都在增加（在英国，在过去的十年中，发病率增加了23％）。口腔癌是一种致命的疾病，经常发生转移性扩散，这是预后不良的最重要预测指标。该研究项目将对控制口腔癌转移的分子途径产生重要知识，鉴于EMT在转移中的核心作用，这可能是其他肿瘤类型的推广。从这项研究中出现的靶标将开发出新的靶向疗法以防止转移。

项目成果

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

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

Highlight: microfluidic devices for cancer metastasis studies

• DOI: 10.1007/s44164-022-00023-y
• 发表时间: 2022-12-01
• 期刊: IN VITRO MODELS
• 作者: Scemama, Alice;Lunetto, Sophia;Biddle, Adrian
• 通讯作者: Biddle, Adrian

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

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