Contacts with macrophages promote an aggressive nanomechanical phenotype of circulating tumor cells in prostate cancer.


Aggressive tumors of epithelial origin shed cells that intravasate and become circulating tumor cells (CTC). The CTCs that are able to survive the stresses encountered in the bloodstream can then seed metastases. We demonstrated previously that CTCs isolated from the blood of prostate cancer patients display specific nanomechanical phenotypes characteristic of cell endurance and invasiveness and patient sensitivity to androgen deprivation therapy. Here we report that patient-isolated CTCs are nanomechanically distinct from cells randomly shed from the tumor, with high adhesion as the most distinguishing biophysical marker. CTCs uniquely co-isolated with macrophage-like cells bearing the markers of tumor-associated macrophages (TAM). The presence of these immune cells was indicative of a survival-promoting phenotype of “mechanical fitness” in CTCs based on high softness and high adhesion as determined by atomic force microscopy (AFM). Correlations between enumeration of macrophages and mechanical fitness of CTCs were strong in patients before the start of hormonal therapy. Single-cell proteomic analysis and nanomechanical phenotyping of tumor cell-macrophage co-cultures revealed that macrophages promoted epithelial (E) -mesenchymal (M) plasticity in prostate cancer cells manifesting in their mechanical fitness. The resulting softness and adhesiveness of the mechanically fit CTCs confer resistance to shear stress and enable protective cell clustering. These findings suggest that selected tumor cells are coached by TAMs and accompanied by them to acquire intermediate E/M status, thereby facilitating survival during the critical early stage leading to metastasis.


Pawel A. Osmulski, Alessandra Cunsolo, Meizhen Chen, Yusheng Qian, Chun-Lin Lin, Chia-Nung Hung, Devalingam Mahalingam, Nameer B Kirma, Chun-Liang Chen, Josephine A Taverna, Michael A Liss, Ian M. Thompson, Tim H.-M. Huang and Maria E Gaczynska.  Cancer Research. 2021 May 29. In Press. doi: 10.1158/0008-5472.CAN-20-3595

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