PhD Thesis Defense: Michael D. Nieskoski

Thursday, May 4, 2017, 2:00–4:00pm

Room 105, Cummings Hall

"Influence of Solid Stress upon Pancreatic Cancer Therapy"

Abstract

Pancreatic adenocarcinoma is the fourth leading cause of cancer death, marked by an exceptionally low 1-year survival rate, and is associated with negligible chemotherapy response and aggressive local proliferation.  The disease exhibits elevated total tissue pressure (TTP) and reduced vascular patency within the solid tumor, limiting most attempts at systemic or targeted therapy delivery. Elevated TTP in pancreatic adenocarcinoma is often associated with stress applied by cellular proliferation and hydrated hyaluronic acid osmotic swelling; however, the causal roles of each of the contributors and the microregional heterogeneity of TTP have yet to be clearly measured and explained.

This thesis work used microcatheter pressure measurements that independently assessed solid stress (SS) and interstitial fluid pressure (IFP) as the components of TTP in pancreatic adenocarcinoma xenograft tumors. IFP was found to be nearly constant at capillary pressure, while TTP values varied considerably depending upon the tumor type.  The origin of this variation was directly correlated to collagen content, and not to hyaluronic acid. Regional analysis of collagen demonstrated high spatial irregularity and complexity, that associated with high spatial variations in pressure on the spatial scale of 100 microns. An elastic Hooke’s Law model was developed to describe the ability of collagen to constrain hyaluronic acid swelling and the results correlated to in-vivo measurements of TTP across several pancreatic tumor lines. Additionally, SS showed a direct inverse correlation with functional vascular area and verteporfin photosensitizer uptake, demonstrating the impediment to systemically delivering therapeutic molecules with increased total tissue hypertension.

As a model test of changing collagen, the pancreatic tumor collagen were enzymatically degraded by direct microinjections of collagenase, to reduce pressure and allow increased perfusion and molecular delivery. A significant decrease in total tissue pressure, and increase in verteporfin photosensitizer uptake was observed, thereby indicating depletion of the stromal barrier could positively impact vascular perfusion and potentiate better systemic delivery of therapeutic treatments. The microregional collagen distributions and the observation of how to measure and damage them was the major outcome of this work.

Thesis Committee

For more information, contact Daryl Laware at daryl.a.laware@dartmouth.edu.