Lamin A/C Deficiency Reduces Circulating Tumor Cell Resistance to Fluid Shear
Stress
Michael J. Mitchell, Ph.D., Celine Denais, Ph.D., Maxine Chan, Zhexiao Wang, M.Eng.,
Jan Lammerding, Ph.D., Michael R. King, Ph.D.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY
Metastasis contributes to over 90% of cancer-related deaths, and is initiated when
cancer cells detach from the primary tumor, invade the basement membrane and enter
the circulation as circulating tumor cells (CTCs). While metastasis is viewed as an
inefficient process with most CTCs dying within the bloodstream, it is evident that some
CTCs are capable of resisting hemodynamic shear forces to form secondary tumors in
distant tissues. We hypothesized that nuclear lamins A and C act as key structural
components within CTCs necessary to resist destruction from elevated shear forces of
the bloodstream. Herein, we show that, compared to non-malignant epithelial cells,
tumor cells are resistant to elevated fluid shear forces in vitro that mimic those within
bloodstream, as evidenced by significant decreases in cellular apoptosis and necrosis.
Upon knockdown of lamin A/C, tumor cell resistance to fluid shear stress was
significantly reduced, with significantly increased cell death compared to parental tumor
cell and non-targeting controls. Interestingly, lamin A/C knockdown increased shear
stress-induced tumor cell apoptosis, but did not significantly affect cellular necrosis.
These data demonstrate that lamin A/C is an important structural component that
enables tumor cell resistance to fluid shear stress-mediated death in the bloodstream,
and may thus facilitate survival and hematogenous metastasis of CTCs.