Role of Gi/o-GPCR signaling in breast cancer progression

Gi/o-GPCR 信号在乳腺癌进展中的作用

• 批准号: 9899948
• 负责人: Songhai Chen
• 金额: $ 46.67万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899948
• 关键词: Address; Antineoplastic Agents; Automobile Driving; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; Breast Epithelial Cells; Cell Surface Receptors; Cells; Coupled; Data; Development; Disease; Drug Targeting; Drug resistance; ERBB2 gene; Effectiveness; Epidermal Growth Factor Receptor; Family; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Genetically Engineered Mouse; Go Alpha Subunit; Human; In Vitro; Knowledge; Lysophosphatidic Acid Receptors; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; PI3K/AKT; Pathway interactions; Patients; Phosphotransferases; Population; Prognostic Marker; Proteins; Proto-Oncogene Proteins c-akt; Recurrence; Resistance; Role; SRC gene; Signal Transduction; Signaling Molecule; Subgroup; Testing; Therapeutic; Therapeutic Intervention; Thrombin Receptor; Transactivation; Transgenic Mice; Trastuzumab; Treatment Protocols; Tumorigenicity; Xenograft Model; Xenograft procedure; breast cancer progression; cancer cell; cancer drug resistance; cancer initiation; cancer therapy; chemokine receptor; clinically relevant; deep sequencing; gain of function; in vivo; malignant breast neoplasm; member; mouse model; multimodality; neoplastic; neoplastic cell; new therapeutic target; outcome forecast; overexpression; patient response; prevent; receptor function; response; self-renewal; stem-like cell; targeted treatment; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic

Project Summary / Abstract G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors that represent the highly desirable drug targets for diverse diseases, including cancer. Despite their importance, our understanding of how GPCRs contribute to tumorigenesis and cancer progression remains limited, because there are over 350 non-sensory GPCRs and many of them are aberrantly expressed in cancer cells. This proposal aims to delineate the function and mechanisms of a subgroup of GPCRs, Gi/o-GPCRs, in regulating the self-renewal and tumorigenic activities of stem cell-like breast tumor-initiating cells (TICs). We will test the idea that targeting Gi/o-GPCRs can eliminate TICs and restore patient response to current therapeutics. As a model of our studies, we focus on ErbB2/HER2-positive breast cancers, because they are highly aggressive and have poor prognosis. HER2-targeted therapy is the preferred treatment for these cancers but drug resistance is the major hurdle. The mechanisms underlying drug resistance remain largely unknown but are attributed to a reservoir of TICs in tumors. TICs may escape therapy in part because they find ways to transactivate HER2 via other pathways—including pathways mediated by GPCRs. Our preliminary studies found Gi/o-GPCRs were overexpressed in human HER2-amplified breast cancer cell lines and mouse TICs from HER2-driven mammary tumors, and were required for growth of TICs in vitro and in vivo. Using our transgenic mouse lines that allow us to upregulate or block Gi/o signaling, in an inducible manner, specifically in mammary epithelial cells, we further showed HER2-driven spontaneous formation of mammary tumors and lung metastases requires Gi/o-GPCR signaling. These exciting data led to our proposal's central hypothesis: HER2-driven breast tumors harbor a reservoir population of TICs that upregulate Gi/o-GPCR signaling; and this hyperactivates EGFR/HER2, permitting TIC self-renewal and ultimately, promoting tumor growth and metastasis. We propose that disrupting Gi/o-GPCR signaling might be a way to ablate TICs, prevent resistance, and maintain effectiveness of HER2-targeted therapeutics . Our proposal uses multimodal approaches, including genetic and patient-derived xenograft mouse models of breast cancer. With this powerful toolkit we will determine the mechanisms of upregulated Gi/o signaling in TICs to increase TIC tumorigenicity and drive cancer development (Aim 1); elucidate if Gi/o- GPCRs function in part through transactivation of EGFR/HER2 via the activation of Gαi/o/c-Src and Gβγ-PI3Kβ signaling axes to drive cancer progression (Aim 2); and finally, test whether blocking Gi/o-GPCR signaling can eliminate TICs and enhance sensitivity to current treatment regimens for HER2+ breast cancer (Aim 3). The overall impact of our studies will be a fundamental advance in our mechanistic understanding of how tumorigenic TICs acquire the ability to transactivate EGFR/HER2 via Gi/o-GPCR signaling. This knowledge may be exploited for finding new ways to eliminate TICs to augment HER2 therapeutics.

项目摘要/摘要 G蛋白偶联受体(GPCRs)是细胞表面最大的受体家族，代表 治疗包括癌症在内的各种疾病的非常理想的药物靶点。尽管它们很重要，但我们的 对GPCRs如何促进肿瘤发生和癌症进展的了解仍然有限，因为 有350多种非感觉性GPCR，其中许多在癌细胞中异常表达。这 该提案旨在界定GPCRs的一个子组--Gi/o-GPCRs在监管方面的功能和机制 干细胞样乳腺肿瘤起始细胞的自我更新和致瘤活性。我们将测试 靶向Gi/o-GPCRs可以消除抽搐并恢复患者对当前治疗方法的反应的想法。 作为我们研究的模型，我们关注ErbB2/HER2阳性乳腺癌，因为它们高度 侵袭性强，预后差。HER2靶向治疗是这些癌症的首选治疗方法，但 耐药性是主要障碍。耐药的机制在很大程度上仍不清楚，但 归因于肿瘤中抽搐的储存库。抽搐可能逃脱治疗的部分原因是他们找到了 通过其他途径反式激活HER2--包括GPCRs介导的途径。 我们的初步研究发现，Gi/o-GPCRs在HER2扩增的乳腺癌中过表达 来自HER2驱动的乳腺肿瘤的细胞系和小鼠TICS，是TICS体外生长所必需的 在活体内。利用我们的转基因小鼠品系，我们可以上调或阻断GI/O信号，在 诱导方式，特别是在乳腺上皮细胞中，我们进一步显示了HER2驱动的自发 乳腺肿瘤和肺转移的形成需要Gi/o-GPCR信号转导。这些令人兴奋的数据导致了 我们建议的中心假设：HER2驱动的乳腺肿瘤中有一个抽搐的储备库人口， 上调Gi/o-GPCR信号；这将过度激活EGFR/HER2，从而允许TIC 自我更新和 最终，促进肿瘤的生长和转移。我们认为，干扰Gi/o-GPCR信号可能是 一种消融抽搐、防止耐药并维持HER2靶向治疗效果的方法 。 我们的提案使用多式联运方法，包括 遗传和患者来源的异种移植小鼠 乳腺癌的模型。有了这个强大的工具包，我们将确定上调GI/O的机制 TICs中增加TIC致瘤性和推动癌症发展的信号转导(目标1)；阐明Gi/o- GPCRs的部分功能是通过激活GαI/o/c-Src和Gβγ-PI3Kβ反式激活EGFR/hER2 驱动癌症进展的信号轴(目标2)；最后，测试阻断Gi/o-GPCR信号是否可以 消除抽搐，提高对HER2+乳腺癌现有治疗方案的敏感性(目标3)。 我们研究的总体影响将是我们从机械上理解如何 肿瘤致病分子通过Gi/o-GPCR信号获得反式激活EGFR/HER2的能力。这一知识 可能被用来寻找新的方法来消除抽搐，以增强HER2疗法。