Novel mechanisms of cancer metastasis

描述（由申请人提供）：结直肠癌是美国第三大流行癌症，每年有近15万新诊断病例。尽管努力改善早期发现和治疗，但每年仍有超过三分之一的患者死于这种疾病。结直肠癌最致命的方面，转移性疾病，也是最不为人所知的。我们对原发性癌症转移转化过程中涉及的潜在分子机制的理解不足，以及我们对癌细胞如何转化缺乏全面的认识，是检测、靶向和根除转移性癌细胞的主要障碍。我们最近的研究表明，在体外和体内系统中，循环巨噬细胞自发地与癌细胞融合。此外，我们有证据表明，由此产生的细胞融合杂交体经历了核重编程，从而保留了巨噬细胞和癌细胞的转录组。我们的观察结果表明，一个有趣的可能性是，巨噬细胞-癌细胞融合代表了一个被低估的过程，可以解释癌细胞如何被重新编程，以表达传统上归因于血细胞的行为，包括迁移、粘附改变和外渗；因此有可能导致转移性疾病。我们的长期研究目标是了解巨噬细胞-癌细胞融合在介导癌症转移扩散中的作用，通过阻断细胞融合促进转移性癌细胞的有效治疗靶点的发展。本研究旨在探讨巨噬细胞-肿瘤融合对疾病转移扩散的生理贡献。基于我们的证据，癌细胞基因组在与巨噬细胞融合后被重编程，我们假设巨噬细胞-肿瘤细胞融合杂种在功能上获得了巨噬细胞样行为，并促进了人类癌症的进展。在转录组分析揭示的见解的指导下，巨噬细胞-癌细胞融合杂交行为和长期特性将在体外和体内系统中进行测试，利用小鼠模型和人体组织的力量。这些研究为癌细胞重编程提供了新的机制，并可能为癌症进展中最致命阶段的治疗干预提供新的线索。

DESCRIPTION (provided by applicant): Colorectal cancer is the third most prevalent cancer in the United States, with nearly 150,000 new cases diagnosed each year. Despite efforts to improve early detection and treatment, over one-third of patients die annually from this disease. The most deadly aspect of colorectal cancer, metastatic disease, is also the least understood. Our inadequate understanding of the underlying molecular mechanisms involved during metastatic conversion of a primary cancer, and our lack of a comprehensive view of how the cancer cell is transformed, are the primary hurdles for detection, targeting and eradication of metastatic cancer cells. We have recently shown that circulating macrophages spontaneously fuse with cancer cells both in vitro and in vivo systems. Further, we have evidence that the resulting cell fusion hybrids have undergone nuclear reprogramming such that they retain both macrophage and cancer cell transcriptomes. Our observations suggest the intriguing possibility that macrophage-cancer cell fusion represents an under-appreciated process to explain how cancer cells become reprogrammed to express behaviors that are traditionally attributed to blood cells, including migration, altered adhesion, and extravasation; and therefore have the potential to drive metastatic disease. Our long-range research goal is to understand the role of macrophage-cancer cell fusion in mediating metastatic spread of cancer to facilitate development of effective therapeutic targets for metastatic cancer cells by blocking cell fusion. This study is designed to investigate the physiologic contribution of macrophage-cancer fusion to metastatic spread of disease. Based upon our evidence that the cancer cell genome is reprogrammed after fusing with macrophages, we hypothesize that macrophage-tumor cell fusion hybrids functionally acquire macrophage-like behaviors and contribute to the progression of cancer in humans. Guided by insights revealed from our transcriptome profiling, macrophage-cancer cell fusion hybrid behavior and long-term properties will be tested in both in vitro and in vivo systems, harnessing the power of both mouse models and human tissues. These studies provide a novel mechanism for cancer cell reprogramming, and may provide new leads for therapeutic intervention of the most deadly stage of cancer progression.