MICA: The network of class I PI3K interacting proteins is dramatically rewired in a PTEN-/- mouse model of prostate cancer. What are the implications?

MICA：I 类 PI3K 相互作用蛋白网络在 PTEN-/- 前列腺癌小鼠模型中发生了显着的重新连接。

• 批准号: MR/R000409/1
• 负责人: Len Stephens
• 金额: $ 99.21万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR000409%2F1
• 关键词: MICA; network; class; PI3K; interacting

Cancer is a disease caused by accumulation of mutations that change the cancer cells in ways that allow them to avoid the normal restraints on their growth, survival and proliferation. Despite this simple truth understanding how mutations give cancer cells an advantage can be difficult to address yet is critical to creating strategies to kill cancer cells selectively. The major problems arise from the fact there are many changes in cancer cells that are merely reactions to the key driving events and actually make no difference to cancer progression. This project aims to understand how loss of a gene that normally resists cancer (PTEN) and is very commonly a key causal event in prostate cancer gives cancer cells an advantage. We have assembled a large amount of unpublished data using a combination of new genetic strategies to dissect signalling inside normal and cancerous mouse prostate cells. This work has revealed a totally unappreciated mechanism by which loss of PTEN can give prostate (or potentially other cell types in which PTEN is lost) new properties that help them avoid normal restraints on their growth, survival and proliferation. The mechanisms work like an in-built growth accelerator that partially bypasses the need for the driver to push on the gas pedal. We propose to do this work using a mouse model of cancer, and cultured cells derived from them, where it is possible to make single mutations and study their impacts in isolation from many other mutations and changes that have accumulated in human cancers. We will test if genetically removing the molecules that constitute the in-built accelerator mechanism slows cancer progression. Through this strategy we can build a detailed understanding of the key events causing or enabling cancer progression and hence focus efforts into creating new therapeutics into right places.

癌症是一种由突变积累引起的疾病，这些突变改变癌细胞的方式，使它们能够避免对其生长，存活和增殖的正常限制。尽管这个简单的事实，理解突变如何给癌细胞带来优势可能很难解决，但对于创造选择性杀死癌细胞的策略至关重要。主要的问题是，癌细胞中的许多变化仅仅是对关键驱动事件的反应，实际上对癌症进展没有影响。该项目旨在了解通常抵抗癌症的基因（PTEN）的丢失如何使癌细胞具有优势，并且是前列腺癌中非常常见的关键因果事件。我们已经收集了大量未发表的数据，使用新的遗传策略的组合来剖析正常和癌变小鼠前列腺细胞内的信号传导。这项工作揭示了一种完全不受重视的机制，通过这种机制，PTEN的丢失可以赋予前列腺（或可能丢失PTEN的其他细胞类型）新的特性，帮助它们避免对生长，存活和增殖的正常限制。这些机制就像一个内置的生长加速器，部分绕过了司机踩油门的需要。我们建议使用小鼠癌症模型和来自它们的培养细胞来做这项工作，在那里可以进行单突变并研究它们的影响，而这些突变和变化与人类癌症中积累的许多其他突变和变化无关。我们将测试基因去除构成内置加速器机制的分子是否会减缓癌症进展。通过这种策略，我们可以详细了解导致或使癌症进展的关键事件，从而集中精力在正确的地方创造新的治疗方法。

项目成果

PI3Kd Forms Distinct Multiprotein Complexes at the TCR Signalosome in Naïve and Differentiated CD4 + T Cells

PI3Kd 在幼稚和分化 CD4 T 细胞的 TCR 信号体上形成独特的多蛋白复合物

• DOI: 10.17863/cam.66145
• 发表时间: 2021
• 作者: Luff D

Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform-selective subunit associations and recruitment to receptors.

• DOI: 10.1073/pnas.1803446115
• 发表时间: 2018-11-27
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Tsolakos N;Durrant TN;Chessa T;Suire SM;Oxley D;Kulkarni S;Downward J;Perisic O;Williams RL;Stephens L;Hawkins PT
• 通讯作者: Hawkins PT