Strategies of mechanical adaptations of circulating tumor cells and properties of their cellular microenvironment have predictive and prognostic biomarker value

Abstract

Mechanically demanding conditions in the blood circulation damage and kill majority of tumor-shed circulating tumor cells (CTCs). Mechanical fitness: a set of mechanical properties detected with atomic force spectroscopy based force spectrometry supports survival of CTCs. We propose that live CTCs isolated from peripheral blood of prostate cancer patients represent distinct strategies of fitness promoting mechanical adaptations to the fluid shear stress. Some of the cells mimicked properties of erythrocytes (high stiffness) or leukocytes (high deformability). The clustering strategy characterized by exceptionally high adhesion is ingenious to CTCs and not found in blood cells. The abundance of CTCs with elevated adhesion has a predictive value for prostate cancer patients starting first round of androgen deprivation therapy. Moreover, a high adhesion score based on individual cells or average patient-specific adhesion is instrumental to stratify recurrent patients that underwent diagnostic imaging by PSMA-PET/CT and clarify inconclusive PSMA scan results. Including contribution of erythrocyte-like strategy broadened the predictive power of CTC mechanophenotyping. Improved biomarking opportunities to predict early castration resistances were noted when the composition of CTC microenvironment was included alongside the mechanical properties. We demonstrated previously that the CTC microenvironment is formed by large cells co-purifying by microfiltration of the blood of cancer patients. Analysis of the association of particular components of CTC microenvironment with the clustering strategy led to pointing at highly adhesive CTC-EMT. However, in the advanced patients adhesiveness of CTC-EMT was surpassed by tumor hybrid cells (THCs), a distinctive kind of invasive species formed by incomplete phagocytosis of CTCs by macrophages. THCs changed their mechanical phenotype and strategy preference with disease progression pointing at the dynamic nature of adaptations of tumor-shed cells to circulation conditions.