Ectopic somatic progression of metastatic breast cancer cells

乳腺癌的转移性复发可能发生在治愈性手术后数月至数十年。我们已经收集了大量的证据表明，乳腺癌的早期转移性传播和异位体细胞进展在许多患者中是非常可能的。在第一个资助期内，我们开发了从乳腺癌患者存档的骨髓载玻片中分离单播散性癌细胞（DCCs）的新方法，从而在分离dcc后实现高质量的全单细胞基因组扩增。我们进一步开始邀请患者对循环肿瘤细胞（ctc）进行分析，这些细胞在经过治疗性手术和骨髓取样数年至数十年后已经出现明显的转移。收集了包括原发肿瘤细胞、dcc和m1期ctc的前三胞胎。第一个结果表明早期传播和意想不到的进化进程路径的复杂性。同时，我们确定了乳腺癌小鼠模型的早期传播和转移形成机制。我们现在将A3的两个方面结合起来，以便更好地理解早期转移形成：对于人类样本，我们将描述早期dcc为了在恶劣环境中产生后代而获得的基因组改变；对于BalbNeuT模型，我们将解决肿瘤细胞内在和微环境诱导的机制，诱导从传播到增殖和集落形成的转变。在A6和C2的生物信息学帮助下，我们将覆盖在小鼠模型和患者中确定的候选通路，以揭示患者早期转移形成的机制。

Metastatic relapse in breast cancer can occur months to decades after curative surgery. We have gathered substantial evidence that metastatic dissemination is early in breast cancer and that ectopic somatic progression is very likely in many patients. During the first funding period we have developed new methods to isolate single disseminated cancer cells (DCCs) from archived bone marrow slides of breast cancer patients enabling high quality whole single cell genome amplification after DCC-isolation. We have further started to invite patients for analysis of circulating tumour cells (CTCs) that now, years to decades after curative surgery and bone marrow sampling, have developed manifest metastasis. First triplets comprising primary tumour cells, DCCs and M1-stage CTCs have been collected. The first results indicate early dissemination and an unexpected complexity of evolutionary progression pathways. In parallel, we identified mechanisms of early dissemination and metastasis formation in a mouse model of breast cancer. We will now combine the two aspects of A3 for a better understanding of early metastasis formation: for human samples we will delineate genomic alterations that are acquired by early DCCs in order generate progeny in hostile environments; for the BalbNeuT model we will address tumor cell-intrinsic and microenvironmentally induced mechanisms that induce a switch from dissemination to proliferation and colony formation. Together with the bioinformatics help from A6 and C2, we will then overlay candidate pathways identified in mouse models and patients to unravel mechanisms of incipient metastasis formation in patients.