Molecular mechanisms underlying circulating tumor cell aggregation

循环肿瘤细胞（CTC）造成持续和持久的威胁，以产生新的转移，尽管在一个特定的时间内， 未知，效率极低。与单个CTC相比，多细胞CTC的簇具有20-100 倍高的转移能力，产生更多的多克隆转移，并与更差的预后相关。我们 以前的研究表明，除了集体迁移和内聚脱落外， 是CTC簇形成、增强癌症干性和多克隆转移的新机制。的 本提案的目的是阐明CD 44和PAK 2促进的细胞凋亡的分子机制。 CTC聚集，确定CTC簇介导的多克隆转移的驱动因素，从而开发 使用多种靶向策略来阻断三阴性乳腺癌的肺转移的原理验证 人PDX和CTC系以及小鼠肿瘤模型。合作团队包括刘慧平博士 （西北大学）在CTC和癌症干细胞的专业知识，乳腺肿瘤学家马西莫博士 Cristofanilli（西北大学），成像专家Constadina Arvanitis博士（西北大学），以及 生物信息学家和结构生物学家Yang Shen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).