C, Frequencies of IHC-detected vascular CTC clusters (% of all CTC events) within breast tumor and distant metastasis sections of seven patients ( n = 9 human tissues) and seven PDX models ( n = 28 mouse tissues listed in Supplementary Table S1). B, IHC staining with a TN PDX breast tumor section for cytokeratin (CK) showing clustered tumor cells within the vasculature (a lower magnification image is shown in Supplementary Fig. A, H&E staining images of CTC clusters (orange arrows) within the vasculature of the lung metastasis (met) sections of TN breast cancer patient CW1 (left) and a TN1 PDX mouse (right). Tumor cell clusters arise from cellular aggregation. Our studies highlight that CD44 + CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. The intercellular CD44–CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44–PAK2 interactions for further activation of FAK signaling. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models.
Circulating tumor cells (CTC) seed cancer metastases however, the underlying cellular and molecular mechanisms remain unclear.
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