Cooperation of oncogenic mutations in the control of malignancy

癌症分子分析的主要动机之一是需要发展合理的 确定有效的癌症治疗方法。这需要发现癌细胞- 具体的药物靶点，以及临床经验表明的药物靶点组合。目标识别， 然而，这是出了名地困难和不可预测。在某种程度上，这是因为细胞调节本质上是 复杂.此外，也已经清楚的是，肿瘤进展与深刻的 控制细胞功能的遗传和代谢网络的变化。现在有广泛的 这将是不可能理解癌症的发展和进展，如果没有 考虑支持正常人体细胞功能的网络及其带来的变化 关于恶性转化。 在我们的研究集中在多步骤致癌的分子机制，我们 已经鉴定了细胞基因组，其在表达或蛋白质活性方面表现出协同作用， 对两个协同致癌突变的联合作用的反应。此外，我们表明，这样的 “协同反应基因”对于癌细胞表型的表达和维持是必需的， 这表明致癌突变至少部分地通过会聚 信号机制。值得注意的是，这些基因可以作为控制多种多样的 细胞过程，如增殖，存活，运动和侵袭，这表明合作， 致癌突变可以通过有限数量的癌症同时影响多种癌细胞特征， 细胞特异性调节过程。 我们的实验方法允许遗传和生物化学分析的监管过程， 这种协同致癌突变通过考虑多种致癌因素来控制癌细胞的行为， 变量在此背景下，我们重点分析激活Ras与肿瘤之间的潜在合作 抑制性p53功能丧失突变经常在多种癌症中发现。我们的研究揭示了 p53功能的丧失通过改变Ras信号传导通路， 整合事件在控制与恶性肿瘤相关的各种细胞特性中发挥关键作用。我们 因此，假设合作反应基因的鉴定以及它们的研究， 作用机制和功能相互关系提供了一个合理的途径来识别癌细胞 脆弱性，特别是对于大部分具有缺陷p53的癌症，这些癌症特别耐药。 常规治疗方案。

One of the main motives for the molecular analysis of cancer is the need to develop rational approaches to the identification of effective cancer treatments. This requires the discovery of cancer cell- specific drug targets and, as clinical experience indicates, drug target combinations. Target identification, however, is notoriously difficult and unpredictable. In part, this is because cell regulation is inherently complex. In addition, it has also become clear that neoplastic progression is associated with profound changes in the genetic and metabolic networks that control the functioning of the cell. There is now broad consensus that it will be impossible to understand the development and progression of cancer without consideration of the networks that support functioning of the normal human cell and the changes brought about by malignant transformation. In our research focusing on the molecular mechanisms underlying multi-step carcinogenesis, we have identified sets of cellular genes that with regard to their expression or protein activity show synergistic responses to the combined action of two cooperating oncogenic mutations. Moreover, we show that such 'cooperation response genes' can be essential for expression and maintenance of the cancer cell phenotype, indicating that oncogenic mutations induce malignant cell transformation at least in part through converging signaling mechanisms. Remarkably, these genes can act as mediators in the control of multiple and diverse cellular processes, such as proliferation, survival, motility and invasiveness, suggesting that cooperating oncogenic mutations simultaneously can affect multiple cancer cell traits through a limited number of cancer cell-specific regulatory processes. Our experimental approach permits genetic and biochemical analysis of the regulatory processes by which cooperating oncogenic mutations control cancer cell behavior through consideration of multiple variables. In this context we focus on analysis of the potent cooperation between activating Ras and tumor suppressor p53 loss-of-function mutations frequently found in a variety of cancers. Our work has revealed that loss of p53 function profoundly affects the quality of Ras signal transmission through altering signal integration events that play key roles in controlling various cell properties associated with malignancy. We thus hypothesize that identification of cooperation response genes together with investigation of their mechanisms of action and functional inter-relationships provides a rational path to identification of cancer cell vulnerabilities, particularly for the large fraction of cancers with defective p53 that are particularly resistant to conventional treatment regimens.