Biased chemokine receptor signaling in cancer progression

癌症进展中偏向的趋化因子受体信号传导

• 批准号: 10541844
• 负责人: Michael B Dwinell
• 金额: $ 38.38万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541844
• 关键词: Agonist; Amino Acids; Arrestins; Binding; Binding Sites; Biochemical; Biological Response Modifiers; Biomimetics; Bone Marrow; Bone neoplasms; CXCR4 Receptors; CXCR4 Signaling Pathway; CXCR4 gene; Carcinoma; Cell Culture Techniques; Cell Death; Cells; Concept Formation; Coupled; Cytotoxic T-Lymphocytes; Data; Destinations; Development; Diagnosis; Dimerization; Disseminated Malignant Neoplasm; Engineering; Epithelial Cells; Fostering; G Protein-Coupled Receptor Signaling; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetically Engineered Mouse; Goals; Growth; Immune; Immune Evasion; Immunity; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediating; Mediator; Modeling; Molecular Conformation; Movement; Neoplasm Metastasis; Nonmetastatic; Normal Cell; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Physiological; Pre-Clinical Model; Proliferating; Public Health; Publishing; Receptor Signaling; Recurrence; Reporting; Research; Residual Cancers; Role; Signal Transduction; Stromal Cell-Derived Factor 1; Stromal Cells; Structural Models; Structure; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Promotion; Variant; Work; Xenograft Model; anti-tumor immune response; antitumor agent; antitumor effect; beta-arrestin; cancer cell; cancer therapy; cell killing; chemokine; chemokine receptor; chemotherapy; design; dimer; efficacy testing; experimental study; extracellular; gemcitabine; immune checkpoint blockade; in vivo; migration; molecular imaging; monomer; mouse model; mutant; neoplastic cell; novel; novel strategies; pancreatic cancer cells; pancreatic cancer model; permissiveness; pleiotropism; pre-clinical; prevent; receptor; spectroscopic imaging; success; synergism; therapy resistant; trafficking; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic

Project Summary Pancreatic cancer is a uniformly lethal form of cancer with patients rarely surviving two years after diagnosis due to pronounced metastasis, immune suppression and evasion, desmoplasia, and unchecked tumor proliferation that together confer therapeutic resistance. Cancer metastatic potential is mediated by the G protein-coupled chemokine receptor CXCR4. The chemokine CXCL12 is the cognate ligand for CXCR4 and is an immune mediator produced by both stromal cells in the tumor microenvironment and normal cells at metastatic destinations. While a wealth of reports attribute elevated CXCR4 expression with pro-tumorigenic effects in numerous cancers, the precise mechanistic roles for CXCR4 and CXCL12 in non-metastatic pathways of pancreatic cancer progression remain poorly understood. Our published and exciting preliminary data have revealed a novel mechanism whereby CXCL12 can either promote or inhibit tumor progression and metastasis based on its ability to activate CXCR4 as a monomer or dimer. In pursuit of determining the mechanism behind CXCR4-mediated cancer progression, we have engineered a locked monomer variant of CXCL12 that acts as a balanced agonist at CXCR4, activating the entirety of its G protein and -arrestin signaling repertoire, as well as a locked dimer biased agonist variant which activates only a subset. We hypothesize that biased signaling at CXCR4 prevents tumor migration and progression while attracting cytotoxic T lymphocytes from the bone marrow and tumor periphery to infiltrate the tumor and kill cancer cells. The overall goal of this proposal is to harness biased agonist signaling as a multi-pronged anti-tumor approach to abrogate pancreatic cancer progression. Aim 1 will use genetically engineered mouse models of pancreatic cancer to analyze the in vivo influence of biased agonist signaling in tumor progression. Aim 2 will use transgenic mouse models and cell culture approaches to investigate the sparsely-studied effects of biased signaling on immune cell trafficking, infiltration, and tumor cell killing in the tumor microenvironment. Aim 3 will delve into the amino-acid level interactions between CXCL12 agonists with CXCR4 receptor to determine the mechanisms responsible for anti-tumor ligand biased and tissue biased signaling. The overall impact of the proposed work is that we will reveal a targetable structural and biochemical biased agonist signaling mechanism that explains the pleiotropic effects of CXCL12 and CXCR4 in cancer.

项目概要 胰腺癌是一种致命的癌症，患者在两年后很少能存活 由于明显的转移、免疫抑制和逃避、结缔组织增生和 不受控制的肿瘤增殖共同导致了治疗耐药性。癌症转移潜力 由 G 蛋白偶联趋化因子受体 CXCR4 介导。趋化因子 CXCL12 是 CXCR4 的同源配体，是肿瘤中两种基质细胞产生的免疫介质 转移目的地的微环境和正常细胞。虽然大量报告指出 CXCR4 表达升高，在多种癌症中具有促肿瘤作用， CXCR4 和 CXCL12 在胰腺癌非转移途径中的机制作用 进展仍知之甚少。我们发布的令人兴奋的初步数据揭示了 CXCL12促进或抑制肿瘤进展和转移的新机制 基于其将 CXCR4 作为单体或二聚体激活的能力。为了追求确定 为了了解 CXCR4 介导的癌症进展背后的机制，我们设计了一个锁定单体 CXCL12 的变体，作为 CXCR4 的平衡激动剂，激活其整个 G 蛋白 和 -arrestin 信号传导库，以及激活的锁定二聚体偏向激动剂变体 只是一个子集。我们假设 CXCR4 的偏向信号传导可阻止肿瘤迁移并 进展，同时吸引来自骨髓和肿瘤周围的细胞毒性 T 淋巴细胞 浸润肿瘤并杀死癌细胞。该提案的总体目标是利用偏向激动剂 信号传导作为一种多管齐下的抗肿瘤方法来消除胰腺癌的进展。目标1 将使用胰腺癌基因工程小鼠模型来分析其体内影响 肿瘤进展中偏向的激动剂信号传导。目标2将使用转基因小鼠模型和细胞 培养方法研究偏向信号对免疫细胞的影响 肿瘤微环境中的运输、浸润和肿瘤细胞杀伤。目标 3 将深入研究 CXCL12 激动剂与 CXCR4 受体之间的氨基酸水平相互作用，以确定 负责抗肿瘤配体偏向和组织偏向信号传导的机制。总体影响 拟议工作的重点是我们将揭示一种可靶向的结构和生化偏向激动剂 信号机制解释了 CXCL12 和 CXCR4 在癌症中的多效性作用。

项目成果

Mitochondria-targeted magnolol inhibits OXPHOS, proliferation, and tumor growth via modulation of energetics and autophagy in melanoma cells.

• DOI: 10.1016/j.ctarc.2020.100210
• 发表时间: 2020
• 期刊: Cancer treatment and research communications
• 作者: Cheng G;Hardy M;Zielonka J;Weh K;Zielonka M;Boyle KA;Abu Eid M;McAllister D;Bennett B;Kresty LA;Dwinell MB;Kalyanaraman B
• 通讯作者: Kalyanaraman B

p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.

• DOI: 10.1158/0008-5472.can-19-3281
• 发表时间: 2020-08-15
• 期刊: Cancer research
• 影响因子: 11.2

Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth.

• DOI: 10.1158/0008-5472.can-21-0483
• 发表时间: 2021-10-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Geethadevi A;Nair A;Parashar D;Ku Z;Xiong W;Deng H;Li Y;George J;McAllister DM;Sun Y;Kadamberi IP;Gupta P;Dwinell MB;Bradley WH;Rader JS;Rui H;Schwabe RF;Zhang N;Pradeep S;An Z;Chaluvally-Raghavan P
• 通讯作者: Chaluvally-Raghavan P

Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance.

• DOI: 10.1038/s41698-021-00152-9
• 发表时间: 2021-03-02
• 期刊: NPJ precision oncology
• 影响因子: 7.9
• 作者: Parashar D;Geethadevi A;McAllister D;Ebben J;Peterson FC;Jensen DR;Bishop E;Pradeep S;Volkman BF;Dwinell MB;Chaluvally-Raghavan P;James MA
• 通讯作者: James MA