Kinetics of Cellular Aggregation Mediated through Different Kind of Interaction Mechanisms

Abstract

Metastasis is the primary cause of cancer related mortality and morbidity. The circulating tumor cells (CTCs) are shed by epithelial-origin tumors, intravasate assisted by tumor-associated macrophages (TAMs) and travel with blood. A few CTCs extravasate and seed metastasis. However, to reach their destination CTCs have to adapt to hostile for them circulation environment. Previously, we found that the nanomechanical properties of CTCs isolated from prostate cancer patient blood point at CTCs endurance and invasiveness associated with EMT (epithelial-mesenchymal transition). in turn these properties correlated with the patients' sensitivity to androgen deprivation therapy. Here we present evidence that CTCs uniquely co-isolate with macrophage-like cells similar to tumor-associated macrophages (TAMs). We determined with atomic force microscopy (AFM) that pronounced presence of these immune cells was associated with high softness and high adhesion of CTCs. Such survival-promoting phenotypes were related to mechanical fitness and invasiveness in CTCs and could be especially strong in patients starting hormonal therapy. Next, we aimed to recapitulate the tumor cells -macrophages interactions in cell culture using prostate cancer cell lines. Nanomechanical phenotyping and single-cell proteomic analysis showed that the presence of TAM like cells promoted hybrid EMT that increased the mechanical fitness of CTCs. We postulate that to acquire hybrid EMT, certain CTCs are coached by TAMs during their co-migration through the bloodstream. The resulting well-mechanically fit CTCs survive the critical early stage of circulation thanks to softness bestowing resistance to shear stress, and adhesiveness enabling protective cell clustering.