Mechanics of cancer metastasis
We have shown that cancer cells (human colon carcinoma, HCT-8) can exhibit metastasis like phenotype in vitro induced solely by an appropriate mechanical softness of the microenvironment. This rather remarkable phenotype is observed when HCT-8 cells are cultured on gels with intermediate-stiffness (physiologically relevant 21 kPa- 47 kPa), but not on very soft (1 kPa) and hard (3.6 GPa) substrates. The cell-cell adhesion molecule E-Cadherin, a metastasis hallmark, decreases 3-5 fold on cell membranes in concert with disassociation. Both specific and non-specific cell adhesion (measured by a Bio-MEMS force sensor) decrease once the cells have disassociated. After re-culturing the disassociated cells on fresh substrates, they retain the disassociated phenotype regardless of substrate stiffness. These results indicate that during culture on appropriate mechanical microenvironment, HCT-8 cells undergo a stable cell-state transition with increased in vitro metastasis-like characteristics as compared to parent cells grown on standard, stiff tissue culture dishes. When implanted in mouse spleen, the dissociated cells show higher tumorigenicity compared to the parent cells. This novel finding suggests the onset of metastasis may be fundamentally linked to the mechanical microenvironment of the tumor.
Currently, we are addressing the following questions: (1) What is the role of intra-cellular forces in transforming the parent HCT-8 cells to metastatic ones? (2) Can cell forces be used as a marker for drug screening? (3) Is there a mechanical signature in metastatic colon cancer cells from human patients? Can such signature(s) be used for cancer prognosis? These questions are explored in collaboration with Carle Foundation Hospital, Presence Hospital and Mayo Clinic.