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

癌症是一种由突变积累引起的疾病，这些突变改变了癌细胞，使它们能够避开对其生长、生存和增殖的正常限制。尽管这是一个简单的事实，但了解突变如何给癌细胞带来优势可能是很难解决的，但对于创造选择性杀死癌细胞的策略至关重要。主要问题产生于这样一个事实，即癌细胞中的许多变化只是对关键驱动事件的反应，实际上对癌症的进展没有影响。这个项目旨在了解一种正常抵抗癌症的基因(PTEN)的缺失是如何给癌细胞带来优势的。PTEN通常是前列腺癌的一个关键原因。我们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的小鼠前列腺细胞内的信号。这项工作揭示了一种完全未知的机制，即PTEN的缺失可以给前列腺癌(或其他类型的PTEN缺失的细胞)新的特性，帮助它们避免正常的生长、存活和增殖限制。这些机制的工作原理就像一个内置的增长加速器，在一定程度上绕过了司机推油门的需要。我们建议使用癌症的小鼠模型和从它们衍生的培养细胞来完成这项工作，在那里可以进行单一突变，并从人类癌症中积累的许多其他突变和变化中分离出来研究它们的影响。我们将测试通过基因移除构成内置加速器机制的分子是否可以减缓癌症的进展。通过这一战略，我们可以建立对导致或促进癌症进展的关键事件的详细了解，从而将重点放在为正确的地方创造新的疗法上。

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 We have assembled a large amount of unpublished data using a combination of new genetic strategies to dissect signalling inside normal and cancerous mouse prostate cells.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.