Figure 12.

Key unknowns and future directions. (A) How does the genotype of the PDAC cancer cell affect fibrosis? (B) Are CAF subpopulations interconvertible, and what determines interconvertibility? (C) What distinguishes good from bad stroma, and how does a particular mix of CAF subpopulations determine stromal behavior? (D) How do stromal composition and architecture affect nanomedicine delivery and efficacy? How do signaling at the cellular level and stromal composition/architecture interrelate? (E) How do nanomedicines penetrate the tumor stroma? What is their route of passage? (F) What are the mechanisms governing the nanoparticle–bio interface, and how do these mechanisms affect the ancillary effects of nanomedicine? Are the nanomedicines safe in the long term? (G) What can be combined with strategies targeting the fibrotic barrier to achieve synergy? (H) Which model should be used to study fibrotic barriers?