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

项目摘要 癌症是由一个复杂的基因和途径网络驱动的。几十年的研究发现 多种癌基因和肿瘤抑制因子，可推动细胞转化和恶性转化。然而，在那里 有许多对癌细胞生存至关重要的基因，但它们本身并没有发生突变。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 识别和靶向这些基因，以提供解除癌细胞武装和使其对治疗敏感的替代途径 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变量 和不断变化的环境。通过检测单个细胞的不同转录调控状态 乳房上皮组织的三维培养模型，我们的实验室发现了一个重要的调控途径， 一种常见的上游调节因子NRF2。Nrf2是一种已知的肺癌癌基因，但 转录因子在乳腺癌中并不常见。在这项提案中，我正在研究非政府组织 癌基因NRF2在一种侵袭性乳腺癌亚型中的作用，希望确定新的治疗策略 阻止这种非致癌基因的上瘾。该项目需要三个相互关联的目标：1)确定功能 NRF2对三阴性乳腺癌细胞生长、组织和存活的重要性；2)量化 并模拟了NRF2动态的更广泛的网络环境；3)测试NRF2对乳房的影响 体内的肿瘤发生。这些目标集中在非癌基因NRF2上，它被经典地称为 抗氧化剂转录因子。大多数与癌症相关的NRF2研究都集中在基因突变上 转录因子及其相关途径。我们的假设是，还有另一层NRF2- 在没有突变的情况下发生在单细胞水平上的驱动肿瘤发生。详细了解NRF2 监管可能会使新的策略能够破坏这种非癌基因成瘾，并使癌细胞对 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.