Decoding the mechanisms of cell-cell fusion

解读细胞与细胞融合的机制

• 批准号: 10183001
• 负责人: Elizabeth H Chen
• 金额: $ 4.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-04 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183001
• 关键词: Biological Markers; Biopsy; Birth Place; Cancer Biology; Cell fusion; Cells; Cessation of life; Disseminated Malignant Neoplasm; Distant; Epithelial; Epithelium; Genes; Human; Hybrid Cells; Hybrids; In Vitro; Invaded; Leukocytes; Malignant Neoplasms; Mediating; Modeling; Molecular; Neoplasm Metastasis; Organ; Physiological; Primary Neoplasm; Process; Research; Role; Site; Supporting Cell; Tissues; Traction; Uncertainty; cancer cell; cancer therapy; cancer type; live cell imaging; macrophage; migration; neoplastic cell; novel therapeutic intervention; novel therapeutics; peripheral blood; single-cell RNA sequencing

Project Summary Cancer metastasis accounts for approximately 90% of cancer-associated deaths, yet the mechanisms underlying this process remain the least understood aspect of cancer biology. During metastasis, tumor cells spread from the primary tumor to surrounding tissues and to distant organs. The most intriguing aspect of cancer metastasis is that despite the epithelial origin of most primary tumors, these tumor cells gain the ability to detach, invade and migrate, such that they can escape their birth place and reach a distant site. What induces such dramatic changes in the primary tumor cells? An interesting possibility is that cancer cells may acquire their migratory potential by fusing with migratory cells, such that the many genes expressed by the latter can be hijacked by cancer cells to promote their migration. Such cancer cell fusion hypothesis has been around for over a century, and the migratory cells are proposed to be leukocytes, such as macrophages. Indeed, various types of cancer cells have been shown to fuse with macrophages in vitro. Moreover, hybrid cells with biomarkers of both cancer cells and leukocytes have been observed in human cancer biopsies and peripheral blood. However, the percentage of the cancer cell-macrophage hybrids indicated by double positive biomarkers is relatively low (1- 20%), raising questions about the physiological relevance of cancer cell-macrophage fusion (CMF) in cancer metastasis. In addition, no one has observed CMF at the primary tumor site, and the molecular mechanism underlying such fusion remains completely unknown. Therefore, the CMF model has gained little traction in the metastasis field to date. Despite these uncertainties, the presence of CMF in various metastatic cancers, albeit detected at a low level, makes the model appealing nevertheless. Moreover, it is well known that the intrinsically fusion-prone macrophages can infiltrate the TME and settle right next to cancer cells, making CMF physically possible. I propose to detect the presence of cancer cell-macrophage hybrid using single cell RNAseq, visualize cancer cell-macrophage fusion using live cell imaging, and identify the molecular components mediating cancer cell-macrophage fusion. If definitive evidence can be obtained to support the CMF model, this will bring about a paradigm shift in our understanding of cancer metastasis and provide basis for novel therapeutic approaches for cancer treatment.

项目摘要 癌症转移约占癌症相关死亡的90％，但其基础机制 这个过程仍然是癌症生物学的最不知情的方面。在转移期间，肿瘤细胞从 周围组织和远处器官的原发性肿瘤。癌症转移最吸引人的方面 是，尽管大多数原发性肿瘤的上皮起源都是上皮的，但这些肿瘤细胞具有分离的能力，侵入 并迁移，以便他们可以逃脱出生地并到达遥远的地点。是什么引起这种戏剧性的 原发性肿瘤细胞的变化？一个有趣的可能性是癌细胞可能会获取其迁移 通过与迁移细胞融合的潜力，使后者表达的许多基因可以被劫持 癌细胞促进其迁移。这种癌细胞融合假说已经存在了一个多世纪， 并认为迁移细胞为白细胞，例如巨噬细胞。确实，各种类型的癌症 细胞已显示在体​​外与巨噬细胞融合。此外，具有两种癌症生物标志物的杂化细胞 在人类癌症活检和外周血中已经观察到细胞和白细胞。但是， 双阳性生物标志物指示的癌细胞巨噬细胞杂种的百分比相对较低（1- 20％），提出有关癌细胞巨噬细胞融合（CMF）生理相关性的问题 转移。此外，没有人在原发性肿瘤部位观察到CMF，分子机制 这种融合的基础仍然是完全未知的。因此，CMF模型在 迄今为止的转移场。尽管存在这些不确定性，但在各种转移性癌症中存在CMF，尽管 检测到低水平，使该模型具有吸引力。而且，众所周知 容易融合的巨噬细胞可以渗入TME并在癌细胞旁边定居，使CMF物理化 可能的。我建议使用单细胞RNASEQ检测癌细胞摩噬细胞杂种的存在，可视化 使用活细胞成像的癌细胞巨噬细胞融合，并鉴定介导癌症的分子成分 细胞巨噬细胞融合。如果可以获得确定的证据以支持CMF模型，这将带来 我们对癌症转移的理解的范式转移，为新颖的治疗方法提供了基础 癌症治疗。