Molecular mechanisms underlying circulating tumor cell aggregation

循环中的肿瘤细胞(CTCs)构成持续和持久的威胁，以创造新的转移，尽管在 未知，效率极低。与单个CTC相比，多细胞CTC集群具有20-100个 转移能力越高，多克隆转移越多，预后越差。我们的 以前的研究发现，除了集体迁移和凝聚脱落外，肿瘤细胞聚集 是CTC簇形成、增强肿瘤干细胞和多克隆转移的新机制。这个 这项建议的目的是阐明CD44和PAK2促进的分子机制 CTC聚集，确定CTC簇介导的多克隆转移的驱动因素，从而发展 原则证明靶向策略阻断三阴性乳腺癌的肺转移 人PDX和CTC细胞系以及小鼠肿瘤模型。合作团队包括刘惠平博士 (西北大学)乳腺肿瘤学家马西莫博士拥有CTC和癌症干细胞方面的专业知识 Cristofanilli(西北大学)，成像专家Constadina Arvantis博士(西北大学)，以及 生物信息学家和结构生物学家杨慎博士(德克萨斯A&M)。

Circulating tumor cells (CTCs) pose continuous and persistent threats to create new metastases albeit at an unknown, extremely low efficiency. Compared to single CTCs, clusters of multicellular CTCs possess 20-100 times higher metastatic capacity, create more polyclonal metastasis, and correlate with worse prognosis. Our previous studies identified that in addition to collective migration and cohesive shedding, tumor cell aggregation is a new mechanism for CTC cluster formation, enhancing cancer stemness and polyclonal metastasis. The objectives of this proposal are to elucidate the molecular mechanisms underlying CD44 and PAK2-promoted CTC aggregation, identify the drivers of CTC cluster-mediated polyclonal metastasis, and therefore develop proof-of-principle targeting strategies to block lung metastasis of triple negative breast cancer, using multiple human PDXs and CTC lines as well as mouse tumor models. The collaborative team includes Dr. Huiping Liu (Northwestern University) with expertise in CTC and cancer stemness, breast oncologist Dr. Massimo Cristofanilli (Northwestern University), imaging expert Dr. Constadina Arvanitis (Northwestern University), and bioinformaticist and structural biologist Dr. Yang Shen (Texas A & M).