Abstract A36: Study of stromal mechanoregulation of tumor metabolism and growth dynamics

Abstract

Abstract As tumors develop and mature they are subjugated to compressive forces and a rigid stroma. This is particularly true in pancreatic cancer where its defining feature is a particularly rigid and fibrous stroma. The mechanical properties of the stroma can have a large influence on the growth behavior and invasiveness of tumors. An intriguing recent example of this is that the PI3K pathway is activated via integrin engagement on a rigid stroma and can affect some metabolic pathways. What makes this exciting is that both the stromal stiffness and reprogrammed metabolism have long been known to be features of cancer and this showed that these features may be intertwined in a feedback loop. From another angle, tumors are subjugated to high compressive forces and many have shown that this force can alter spheroid growth dynamics and shift cells to a more invasive phenotype. While compressive stress on spheroid growth certainly influences its growth dynamics, it is unclear whether it is due to stress or strain on the spheroid. Additionally, it implicates compressive force in altering the cellular metabolism as well. Going a step further, extracellular acidity is a well-known phenotype of solid tumors and is intrinsically linked to an altered metabolism. To study this feedback loop between stromal mechanical properties and metabolism/acidity we will utilize two different models alongside the pH dependent fluorophore, SNARF. The first is a hybrid gel model that is constructed of a base polyacrylamide (PA) layer that is covalently bound to select ECM proteins such as matrix gel and collagen. The second is a spheroid embedded in agarose model in which a base coat of agarose is applied to the bottom of each well in a multiwall plate and after setting, an ungelled mixture of spheroids, agarose and fluorescently labelled latex beads are poured over the base coat and allowed to set. The agarose is bio inert and cannot be broken down by cells. Thus it effectively acts like a compressible, non-integrin activating, isotropic media that completely surrounds the embedded spheroid. To study the cell packing density we will explore a model that predicts strain on an embedded spheroid due to compressive stress drives the cell density in spheroids. To experimentally explore this model, we will use the spheroid embedded in agarose model and vary starting implanted spheroid sizes, but remove them from the agarose at identical stress levels. All of this together will lead us to a better understanding of how the cell metabolism/pHe and tumor cell packing are mechanoregulated by the stroma. Citation Format: Michael Anderson, Jonathan Celli, Hamid El-Hamidi. Study of stromal mechanoregulation of tumor metabolism and growth dynamics. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A36.