Extracellular Compressive Stress as a Determinant of Tumor Growth and Chemotherapy Response in Multicellular Spheroid of Pancreatic Cancer

Pancreatic cancer remains the fourth leading cause of cancer related death with approximately 5% five-year survival and 5 months of median survival. It is predicted to be the second largest cause of cancer deaths by 2030. The survival rate of pancreatic cancer has stayed single digit and has not improved over the past 40 years. Therefore, a novel potential treatment for pancreatic cancer is urgently needed. In our current study we aimed to investigate the role of compressive stress on pancreatic cancer spheroids growth and the therapeutic response. The current study focuses on how cell behavior is controlled by the biophysical properties of the extracellular matrix (ECM). To investigate the role, agarose as a linear polymer scaffold is used with variable concentration in order to change the stiffness of the extracellular environment, without introducing biochemical interactions. To know more about the effect of compressive stress on tumor growth, 3D cell culture of pancreatic cancer adenocarcinoma has been adopted, embedding in agarose and on the bed of agarose. A positive correlation between the spheroids initial volume and the final volume in free condition was obtained. The spheroid volume growth obeys the Gompertz law. This is supported by time lapse imaging and brightfield microscopy of individual spheroid in each condition. The results suggest that increasing the concentration of agarose, reversibly decreases the pancreatic cancer spheroids volume growth. Comparison of spheroids response to chemotherapy under each condition showed that although increasing the concentration of agarose decreases the spheroids growth without a change in proliferation rate, yet it weakens the chemotherapy responses. Taking together current results suggest that growth limiting compressive stress leads to a drug resistant phenotype. Mechanical compression results in diminished drug responsiveness, and spheroids in high stiffness of agarose are less responsive to chemotherapy