Decoding the mechanisms of cell-cell fusion

项目摘要 癌症转移约占癌症相关死亡的90%，但其背后的机制 这一过程仍然是癌症生物学中最鲜为人知的方面。在转移过程中，肿瘤细胞从 转移到周围组织和远处器官的原发肿瘤。癌症转移最耐人寻味的方面 尽管大多数原发肿瘤起源于上皮，但这些肿瘤细胞获得了分离、侵袭 并迁徙，这样它们就可以逃离出生地，到达遥远的地方。是什么导致了如此戏剧性的 原发肿瘤细胞的变化？一种有趣的可能性是癌细胞可能获得它们的迁移性 通过与迁移细胞融合而具有潜力，从而后者表达的许多基因可以被 来促进癌细胞的迁移。这种癌细胞融合假说已经存在了一个多世纪， 而迁移细胞被认为是白细胞，如巨噬细胞。事实上，各种类型的癌症 在体外，细胞已经被证明可以与巨噬细胞融合。此外，带有这两种癌症生物标志物的杂交细胞 在人类癌症活检组织和外周血中已经观察到细胞和白细胞。然而， 双阳性标记物所显示的癌细胞-巨噬细胞杂交体的比例较低(1- 20%)，引发了关于癌细胞-巨噬细胞融合(CMF)在癌症中的生理学相关性的问题 转移。此外，还没有人观察到CMF在原发肿瘤部位的存在及其分子机制 这种融合背后的原因仍是完全未知的。因此，CMF模型在 到目前为止的转移字段。尽管有这些不确定性，CMF在各种转移性癌症中的存在，尽管 在较低的水平上检测到，使该模型仍然具有吸引力。此外，众所周知，本质上 易于融合的巨噬细胞可以渗透到TME中，并在癌细胞旁边定居，从而在物理上形成CMF 有可能。我建议使用单细胞RNAseq，Visualize来检测癌细胞-巨噬细胞杂交的存在 利用活细胞成像技术进行癌细胞-巨噬细胞融合，并鉴定与癌症相关的分子成分 细胞-巨噬细胞融合。如果能够获得确凿的证据来支持CMF模型，这将带来 我们对癌症转移理解的范式转变，并为新的治疗方法提供基础 癌症治疗。

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.