Fig. 7: New therapeutic strategy: Ablate metastasis by overwhelming intrinsic machinery to prevent polarization.

A. Pancreatic cancer progression is histologically defined by a series of cell shape change events from cuboidal epithelial cells (normal), through pseudo-stratified epithelial layers (PanIn), to disorganized and prolific cell growth (cancer). B. These changes are concomitant with genetic lesions and alterations in protein expression, including those proteins that define the mechanoresponsive machinery in PDAC, primarily myosin IIA, myosin IIC, α-actinin-4, and filamin B. These changes in mechanoresponsive machinery have (C) significant implications on cell behavior moving the system from a stable state with high cellular adhesion, low motility, and set polarity, to an adaptive state with low adhesion, high motility, and altered polarity. D. Common therapeutic approaches have primarily involved inhibiting key proteins. This loss of activity is not a viable approach for the PDAC mechanobiome because it leads to uncontrolled growth and dissemination as seen in myosin IIA inhibition or knockdown. Instead, we propose activating or overwhelming the system with mechanical modulators such as 4-HAP which revert the system to a more wildtype-like phenotype, reducing the dynamics of the system without promoting uncontrolled growth.