Investigating the role of melanoma-adipocyte cell junctions in heterotypic communication and tumor progression

研究黑色素瘤-脂肪细胞连接在异型通讯和肿瘤进展中的作用

• 批准号: 10750292
• 负责人: Sarah Perlee
• 金额: $ 4.77万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-13 至 2026-07-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750292
• 关键词: Adhesions; Adipocytes; Adipose tissue; Attention; Binding; Biological Assay; CD146 antigen; CRISPR/Cas technology; Cell Adhesion Molecules; Cell Communication; Cell Line; Cell physiology; Cell-Cell Adhesion; Cells; Coculture Techniques; Communication; Communications Media; Connexin 43; Connexins; Coupled; Coupling; Cyclic AMP; Cyclic Nucleotides; Data; Dermal; Disease; Distant; Dyes; Endothelial Cells; Engineering; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Fishes; Gap Junctions; Goals; Growth; Human; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Intercellular Junctions; Invaded; Ions; Knock-out; Knowledge; Lipase; Lipids; Lipolysis; Malignant Neoplasms; Mediating; Mediator; Melanoma Cell; Metabolic Pathway; Molecular; Neoplasm Metastasis; Organ; Outcomes Research; Pathway interactions; Patients; Phosphorylation; Play; Process; Protein Isoforms; Proteins; Role; Signal Pathway; Signaling Molecule; Skin; Skin Cancer; Source; Subcutaneous Tissue; System; Testing; Triglycerides; Tumor Cell Invasion; Tumor Promotion; Work; Zebrafish; autocrine; cancer cell; cancer therapy; cell type; connexin 45; in vivo; in vivo Model; insight; intercellular communication; keratinocyte; melanoma; new therapeutic target; paracrine; subcutaneous; theories; transcriptome sequencing; transplant model; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

PROJECT SUMMARY Melanoma is the most lethal skin cancer. Few treatment options exist for patients with metastatic disease. Upon tumorigenesis, melanoma cells invade into dermal and subcutaneous tissues and then eventually metastasize to distant organs, encountering and interacting with various microenvironmental cell types. The tumor microenvironment plays a significant role in melanoma progression. Lipid-laden cells called adipocytes are located in the subcutaneous layer of the skin. Recent work from our lab demonstrated that adipocytes serve as a source of fatty acids that fuel melanoma growth and invasion. Although melanoma tumors are often in direct contact with adipocytes, the mechanism of melanoma-adipocyte communication is unclear. Our preliminary data identify the presence of gap junctions between melanoma cells and adipocytes. These data point to Adipocyte Cell Adhesion Molecule (ACAM) as a potential mediator of melanoma-adipocyte adhesion. In Aim 1, we will investigate the mechanism of melanoma-adipocyte adhesion and its role in tumor progression. ACAM mediates cell-cell adhesion through homophilic binding. Our own data show that ACAM is upregulated in melanoma cells that are co-cultured with adipocytes. Loss of ACAM in melanoma cells abrogates gap junctional communication with adipocytes. We hypothesize that ACAM is a key regulator of melanoma-adipocyte contact and communication. Using human melanoma cell lines and adipocytes in a co-culture system, we will identify changes in melanoma-adipocyte adhesion and cell-cell communication upon knock out of ACAM. We will engineer adipocyte-restricted ACAM knockout zebrafish to delineate the effects of adipocyte-specific ACAM loss on tumor progression. In Aim 2, we will elucidate the mechanism and functional consequences of melanoma-adipocyte gap junctions. Gap junctions mediate the transfer of ions, small metabolites, and secondary messengers such as cAMP, a key activator of lipolysis, between neighboring cells. We hypothesize that melanoma-adipocyte gap junctions facilitate the direct transfer of signaling molecules between coupled cells, ultimately activating tumor-promoting pathways such as lipolysis. To gain insight into the molecular basis for melanoma-adipocyte gap junctions, we will first identify the connexin(s) composition of these channels. We will also study the role of melanoma-adipocyte gap junctions in lipolysis and tumor progression using an in vivo zebrafish subcutaneous transplant model. By investigating how melanoma cells interact with adjacent adipocytes, we seek to delineate the impact of adipocytes on tumor progression and identify novel therapeutic targets of the tumor microenvironment.

项目摘要 黑色素瘤是最致命的皮肤癌。转移性疾病患者的治疗选择很少。 在肿瘤发生时，黑色素瘤细胞侵入真皮和皮下组织， 转移到远处器官，遇到各种微环境细胞类型并与之相互作用。的 肿瘤微环境在黑色素瘤进展中起重要作用。充满脂质的细胞称为脂肪细胞 位于皮肤的皮下层。我们实验室最近的工作表明， 作为脂肪酸的来源，促进黑色素瘤的生长和侵袭。虽然黑色素瘤通常 在与脂肪细胞直接接触时，黑色素瘤-脂肪细胞通讯的机制尚不清楚。我们 初步数据确定了黑色素瘤细胞和脂肪细胞之间存在缝隙连接。这些数据 指出脂肪细胞粘附分子（ACAM）是黑色素瘤与脂肪细胞粘附的潜在介质。 目的1：探讨黑色素瘤与脂肪细胞粘附的机制及其在肿瘤中的作用 进展ACAM通过嗜同性结合介导细胞-细胞粘附。我们自己的数据显示，ACAM是 在与脂肪细胞共培养的黑素瘤细胞中上调。黑色素瘤细胞中ACAM的丢失 消除了与脂肪细胞的间隙连接通讯。我们假设，ACAM是一个关键的调节器， 黑色素瘤-脂肪细胞接触和交流。使用人黑色素瘤细胞系和脂肪细胞， 共培养系统，我们将确定黑色素瘤脂肪细胞粘附和细胞间通讯的变化， 从ACAM中淘汰。我们将设计脂肪细胞限制性ACAM敲除斑马鱼，以描述 脂肪细胞特异性ACAM丢失对肿瘤进展的影响。在目标2中，我们将阐明机制， 黑色素瘤-脂肪细胞间隙连接的功能后果。缝隙连接介导了 离子，小代谢产物和二级信使，如cAMP，脂肪分解的关键激活剂， 相邻的细胞。我们假设黑色素瘤-脂肪细胞间隙连接促进了 信号分子之间的耦合细胞，最终激活肿瘤促进途径，如 脂肪分解为了深入了解黑色素瘤-脂肪细胞间隙连接的分子基础，我们将首先鉴定 这些通道的连接蛋白组成。我们还将研究黑色素瘤-脂肪细胞间隙的作用 使用体内斑马鱼皮下移植模型研究脂肪分解和肿瘤进展中的连接。通过 研究黑色素瘤细胞如何与邻近的脂肪细胞相互作用，我们试图描绘黑色素瘤细胞的影响， 脂肪细胞对肿瘤进展的影响，并确定肿瘤微环境的新治疗靶点。