Unravelling the Mechanism of the Lung Tumour Suppressor LIMD1 from Cellular Metabolism to Malignant Transformation.

揭示肺肿瘤抑制因子LIMD1从细胞代谢到恶性转化的机制。

• 批准号: MR/N009185/1
• 负责人: Tyson Sharp
• 金额: $ 48.45万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN009185%2F1
• 关键词: Unravelling; Mechanism; Lung; Tumour; Suppressor

Lung cancer has a very poor survival rate; for disease to be detected earlier, and managed and treated better then more needs to be understood about how healthy cells are transformed into cancer cells.Our group has identified a gene called LIMD1 which prevents the transformation of normal, healthy cells into cancer. We have found that LIMD1 is lost from cells as they progress towards becoming cancerous and this is a key step in their transformation. Rapidly dividing cancer cells need a constant supply of energy and exciting new data from our lab have revealed that the loss of LIMD1 from cells affects the way they make this energy, a series of processes broadly called metabolism. Our project has been designed to thoroughly investigate the way in which loss of LIMD1 causes a switch from "normal" cell metabolism to a "cancerous" state. As well as needing a different amount and balance of nutrients, tumours have dramatically reduced supplies of oxygen and this is also linked to the way they adapt to changes in the requirement for energy. In this respect, we have previously shown that LIMD1 is required by cells to sense and adapt to the levels of oxygen around them. Therefore loss of LIMD1 in cancer cells will dramatically affect the way that they respond to changes in oxygen as tumours grow.To best observe the transformation of normal human lung tissue into cancer we have adopted a 3D model of a small portion of tissue representative of the human upper airways. Using this model we will seek to determine which pathways of metabolism LIMD1 loss affects and, importantly, if these pathways give us new markers of early stages of lung cancer and potential targets for chemotherapy.

肺癌的存活率非常低；要想更早地发现疾病，并对其进行更好的管理和治疗，就需要更多地了解健康细胞是如何转化为癌细胞的。我们的团队已经发现了一种名为LIMD1的基因，它可以防止正常的健康细胞转化为癌症。我们发现，LIMD1在细胞癌变的过程中丢失，这是细胞转化的关键一步。癌细胞的快速分裂需要持续的能量供应，来自我们实验室的令人兴奋的新数据表明，细胞中LIMD1的丢失会影响细胞产生能量的方式，这一系列过程被广泛称为新陈代谢。我们的项目旨在深入研究LIMD1的缺失是如何导致细胞从“正常”代谢状态转变为“癌症”状态的。除了需要不同数量和平衡的营养素外，肿瘤还极大地减少了氧气供应，这也与它们适应能量需求变化的方式有关。在这方面，我们之前已经证明了LIMD1是细胞感知和适应周围氧气水平所必需的。因此，癌细胞中LIMD1的丢失将极大地影响它们对肿瘤生长过程中氧气变化的反应方式。为了最好地观察正常人类肺组织转变为癌症的过程，我们采用了代表人类上呼吸道的一小部分组织的3D模型。使用这个模型，我们将试图确定LIMD1丢失影响哪些代谢途径，重要的是，这些途径是否为我们提供了肺癌早期阶段的新标记物和潜在的化疗靶点。

项目成果

Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition.

• DOI: 10.1038/onc.2016.435
• 发表时间: 2017-05-11
• 期刊: Oncogene
• 影响因子: 8
• 作者: Dermit M;Casado P;Rajeeve V;Wilkes EH;Foxler DE;Campbell H;Critchlow S;Sharp TV;Gribben JG;Unwin R;Cutillas PR
• 通讯作者: Cutillas PR

A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.

• DOI: 10.15252/emmm.201708304
• 发表时间: 2018-08
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Foxler DE;Bridge KS;Foster JG;Grevitt P;Curry S;Shah KM;Davidson KM;Nagano A;Gadaleta E;Rhys HI;Kennedy PT;Hermida MA;Chang TY;Shaw PE;Reynolds LE;McKay TR;Wang HW;Ribeiro PS;Plevin MJ;Lagos D;Lemoine NR;Rajan P;Graham TA;Chelala C;Hodivala-Dilke KM;Spendlove I;Sharp TV
• 通讯作者: Sharp TV

Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.

• DOI: 10.1016/j.celrep.2017.06.027
• 发表时间: 2017-07-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Bridge KS;Shah KM;Li Y;Foxler DE;Wong SCK;Miller DC;Davidson KM;Foster JG;Rose R;Hodgkinson MR;Ribeiro PS;Aboobaker AA;Yashiro K;Wang X;Graves PR;Plevin MJ;Lagos D;Sharp TV
• 通讯作者: Sharp TV

LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death.

• DOI: 10.18632/oncotarget.23676
• 发表时间: 2018-01-19
• 期刊: Oncotarget
• 作者: Wang L;Howell MEA;McPeak B;Riggs K;Kohne C;Yohanon JU;Foxler DE;Sharp TV;Moorman JP;Yao ZQ;Ning S
• 通讯作者: Ning S

Expression of polycomb protein BMI-1 maintains the plasticity of basal bronchial epithelial cells.

• DOI: 10.14814/phy2.12847
• 发表时间: 2016-08
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Torr E;Heath M;Mee M;Shaw D;Sharp TV;Sayers I
• 通讯作者: Sayers I