A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures.

摘要: Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS small numbers (<0.05% by cell count) the aggressive MDA-MB-231 breast line, two populations formed: actively proliferating ("growing"; EdU+), and spontaneously quiescent ("dormant"; EdU-). Following treatment a clinically standard chemotherapeutic, cells were eliminated only remained; residual population could then be induced proliferative state ("emergent"; EdU+) physiologically-relevant inflammatory stimuli, lipopolysaccharide (LPS) epidermal growth factor (EGF). Multiplexed proteomic analysis effluent enabled elucidation key processes correlated various tumor states, candidate biomarkers for (either primary or secondary emergence) versus metastatic tissue. Dormancy was found signaling reflective cellular quiescence even more strongly than original tumor-free tissue, whereas nodules presented signatures. Given minimal burden, these markers likely represent changes microenvironment rather cells. A computational decision tree algorithm applied signatures indicated potential clinical discernment each stage blood protein analysis.