Ectopic somatic progression of metastatic breast cancer cells

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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.