Ectopic somatic progression of metastatic breast cancer cells

转移性乳腺癌细胞的异位体细胞进展

• 批准号: 257888265
• 负责人: Professor Dr. Christoph Klein
• 金额: --
• 依托单位: Lehrstuhl für Experimentelle Medizin und Therapieverfahren
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257888265?language=en
• 关键词: Ectopic; somatic; progression; metastatic; breast

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.

乳腺癌的转移性复发可在根治性手术后数月至数十年发生。我们已经收集了大量的证据表明，转移性播散是早期乳腺癌和异位体细胞进展是很可能在许多患者。在第一个资助期内，我们开发了从乳腺癌患者的存档骨髓载玻片中分离单个播散性癌细胞（DCC）的新方法，从而在DCC分离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进行循环肿瘤细胞（CTC）分析，这些细胞在治愈性手术和骨髓取样后数年至数十年已发生明显转移。已经收集了包括原发性肿瘤细胞、DCC和M1期CTC的第一个三联体。第一个结果表明早期传播和进化进展途径的意想不到的复杂性。同时，我们在小鼠乳腺癌模型中确定了早期播散和转移形成的机制。我们现在将结合联合收割机A3的两个方面，以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获得的基因组改变，以便在恶劣的环境中产生后代;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。再加上A6和C2的生物信息学帮助，我们将覆盖在小鼠模型和患者中识别的候选途径，以解开患者早期转移形成的机制。