Abstract 3152: RhoA-myosinII axis protects circulating tumor cells from fluid shear stress-induced damage

Abstract

Abstract Circulating tumor cells (CTCs) are exposed to hemodynamic forces, which have long been thought to be mechanically destructive to CTCs. However, recent studies show that cancer cell lines from diverse histologies exhibit resistance to brief (millisecond) pulses of high-level (750-6400 dyn/cm2) fluid shear stress (FSS), whereas nontransformed epithelial cells are sensitive to this mechanical insult (PMID: 23226552, 26447202). Moreover, exposure of cancer cells to FSS results in cortical stiffening (PMID: 25908902). Herein, we elucidate the mechanism of FSS resistance in cancer cells, and extend these findings to experimental models of CTCs. We show that although some cancer cell lines exhibit elevated levels of membrane repair relative to nontransformed counterparts, intrinsic resistance to plasma membrane damage is a more consistent feature distinguishing cancer cells. FSS resistance is detectable in cancer cells acutely isolated from primary mouse TP53/PTEN mutant prostate tumors, not just a feature of cultured cancer cell lines. Our findings indicate that cancer cells respond to FSS by activation of RhoA-myosinII contractility, which protects them from nanometer-scale damage to the plasma membrane. Moreover, we present evidence that the RhoA myosinII axis protects CTCs from mechanical damage in animal models. Treatment of PC-3 cancer cells with a nontoxic dose of the myosin II inhibitor blebbistatin (20μM; 3h) reduced the number of intact cells arrested in the lung microvasculature immediately following tail vein injection. Additionally, treatment of mice bearing orthotopically implanted, metastatic PC-3 derived prostate tumors with blebbistatin (2.5mg/kg; 3h) acutely reduced steady-state CTC levels by approximately 10-fold. Taken together, our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought. Citation Format: Devon L. Moose, Ben L. Krog, Gretchen Burke, Lei Zhao, Lillian Rhodes, Michael D. Henry. RhoA-myosinII axis protects circulating tumor cells from fluid shear stress-induced damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3152.