The emerging standard of care for patients with inoperable pancreatic cancer (PC) is a combination of gemcitabine and Abraxane, but patient response remains moderate. PC development and metastasis occur in complex settings with reciprocal feedback from micro-environmental cues influencing both disease progression and drug response. In particular, the extracellular matrix (ECM) promotes cell proliferation, metastasis and chemoresistance, however studies assessing chronic ablation of the ECM have yielded conflicting data. We recently demonstrated that transient manipulation of tissue tension via ROCK inhibition with Fasudil disorientates cancer cells and in turn improves chemotherapy efficacy while impairing metastatic spread. Here, in line with this study, we assess whether transient inhibition of hyaluronic acid (HA) in the stroma using PEGPH20 affects pancreatic cancer progression and response to chemotherapy. We used 3D organotypic assays coupled with live FRET imaging to optimise treatment with PEGPH20. In addition, analysis of stromal HA and ECM texture in a human pancreatic tissue microarray was then conducted to identify patients with “high HA” vs “low HA” and monitoring of HA targeting in these samples was achieved using patient-specific organotypic assays.
Our results show that priming of pancreatic tumour with PEGPH20 reestablishes normal tissue homeostasis, impairs cell invasion and improves chemotherapy. We suggest that HA deposition could be used as a biomarker to identify patients that would benefit from stromal HA targeting prior to chemotherapy. Furthermore, we propose that FRET imaging could provide a useful tool in animal models prior to clinical translation.