Single-Cell Misregulation of NRF2 in Basal-like Breast Cancer

项目摘要 癌症是由基因和途径的复杂网络驱动的。几十年的研究发现 各种致癌基因和肿瘤抑制因子，可以驱动细胞转化和恶性。但 有许多基因是癌细胞生存所必需的，但它们本身并不突变。这些“非 癌基因”可以参与各种细胞生存途径，如应激反应，并可能解释 在具有相同驱动突变的肿瘤细胞中观察到的一些异质性。我们怎么能 鉴定并靶向这些基因，以提供替代途径来解除癌细胞的武装并使其对治疗药物敏感， 干预？ 识别“非癌基因”途径的一种方法是评估增殖细胞如何适应可变的细胞因子。 不断变化的环境。通过研究单个细胞在转录调控中的异质性， 乳腺上皮组织的3D培养模型，我们的实验室发现了一个重要的调控途径， 一个共同的上游调节器，NRF 2。NRF 2是肺癌中已知的致癌基因，但是NRF 2基因的突变导致了肺癌的发生。 转录因子在乳腺癌中并不常见。在这一建议中，我正在研究非政府组织的作用， 癌基因NRF 2在乳腺癌的侵袭性亚型中的作用，希望确定新的策略， 破坏这种非致癌基因成瘾。该项目涉及三个相互关联的目标：1）确定功能 NRF 2对三阴性乳腺癌细胞的生长、组织和存活的重要性; 2）定量 并对NRF 2动力学的更广泛网络背景进行建模; 3）测试NRF 2对乳腺癌的影响。 体内肿瘤发生。这些目标集中在非癌基因NRF 2上，NRF 2通常被称为癌基因。 抗氧化转录因子大多数与癌症相关的NRF 2研究都集中在NRF 2基因的突变上。 转录因子和与之相关的途径。我们的假设是，有另一层的NRF 2- 在单细胞水平上发生而没有突变的驱动肿瘤发生。详细了解NRF 2 调控可以使新的策略来破坏这种非癌基因成瘾和重新敏感癌细胞， 他们的环境和化疗。

Project Abstract Cancer is driven by a complex network of genes and pathways. Decades of research have discovered various oncogenes and tumor suppressors that can drive cell transformation and malignancy. However, there are many genes that are essential for cancer cell survival, but are not mutated themselves. These “non- oncogenes” can be involved in various cell-survival pathways such as the stress response, and might explain some of the heterogeneity observed among tumor cells that have the same driver mutations. How can we identify and target these genes to offer alternative routes to disarm and sensitize cancer cells to therapeutic interventions? One way to identify “non-oncogene” pathways is to evaluate how proliferating cells adjust to variable and evolving environments. By examining heterogeneous transcriptional regulatory states of single cells in a 3D culture model of breast epithelial organization, our lab discovered an important regulatory pathway that had a common upstream regulator, NRF2. NRF2 is a known oncogene in lung cancer, but mutations in the transcription factor are uncommon in breast cancer. In this proposal, I am studying the role of the non- oncogene, NRF2, in an aggressive subtype of breast cancer, in the hopes of determining new strategies to disrupt this non-oncogene addiction. This project entails three interrelated aims: 1) to determine the functional importance of NRF2 for growth, organization, and survival of triple-negative breast cancer cells; 2) to quantify and model the broader network context of NRF2 dynamics; 3) to test the impact of NRF2 on breast tumorigenesis in vivo. These aims are focused on the non-oncogene NRF2, which is classically known as an antioxidant transcription factor. Most cancer-related studies of NRF2 have focused on mutations in the transcription factor and the pathway associated with it. Our hypothesis is that there is another layer of NRF2- driven tumorigenesis that occurs on the single-cell level without mutation. A detailed understanding of NRF2 regulation could enable new strategies to disrupt this non-oncogene addiction and re-sensitize cancer cells to their environment and to chemotherapy.