Biophysics of cancer: modelling and assessing physical resistance to therapy

Lead Research Organisation: University of Leeds
Department Name: Physics and Astronomy


This proposal will use organ-on-chip technology and Atomic Force Microscopy (AFM) to investigate the mechanical properties of in vitro cultured microtumours of pancreatic cancer as they develop under physiologically relevant flow conditions and how the mechanical stiffness of these tumours relates to drug resistance. Solid tumours develop in the body to form areas of dense, rigid tissue, similar to that of scar tissue. Within tumours, there is a complex microenvironment of biophysical conditions that determine the progression of the disease and provide physical barriers to drug delivery. Pancreatic cancer is hallmarked by a dense, fibrous tumour mass in which solid stress and hydraulic pressure cause the collapse of blood vessels, the main route for drug delivery. In addition, the high internal pressures act against the movement of drugs into the tumour mass. Yet despite these critically important physical factors, most in vitro testing of drugs is done against cell culture models that neglect these biophysical parameters entirely.

This proposal we will create microtumours of pancreatic cancer by using microfluidic droplet generators to seed pancreatic tumour cell lines into microgels of defined size (500 um) and culture them under continuous flow conditions similar to what the cells would experience in the body, giving them a more natural environment in which to develop. We will use AFM to assess the mechanical rigidity of these tumours as cells proliferate and deposit matrix stiffening components into their microenvironment and compare them to the same tumours grown in static wells in order to determine the role and importance of hydraulic cues in microenvironment development. We will then use the platform to investigate the crucial relationship between the mechanical properties of these microtumours and their resistance to the penetration of drugs into their structure. We expect that the stiffer the microtumour, the less drug uptake will be observed. This will then be correlated to microtumour viability for a complete picture of tumour development and resistance to drug delivery. Lastly, using our innovative approach, we will investigate new routes to facilitate drug uptake in solid tumours by exposing microtumours to agents that actively break down the stiff matrix and potentially increase drug penetration.
Pancreatic cancer remains one of the deadliest modern-day cancers, with 93% of those being diagnosed dying within 5 years.

Current drug treatments for pancreatic cancer are largely ineffective. Only by improving our in vitro models of disease, in which we accurately model the mode of drug resistance, can we improve treatments and patient outcomes. This proposal focussing on pancreatic cancer but will be applicable to all solid tumours.
Description Award is still in the early stages, but so far:

Preliminary results may indicate that pancreatic cancer spheroids grown in the lab extensively remodel the gel matrices they are cultured in to exhibit a particular stiffness, regardless of the starting gel material.
Exploitation Route Other researchers/ scientists working in 3D modelling may reconsider the culture gels they choose and the length of time that they culture spheroids of pancreatic cancer and other solid tumours.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

Description Investigating the toxicity effect of fibre/nanoparticle formulations on pancreatic spheroids in drug delivery 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Growing, characterisation and assessment of Pancreatic spheroids treated with novel fibre/nanoparticle constructs for therapeutic delivery
Collaborator Contribution Provision of the fibre/nanoparticle constructs
Impact No outcomes yet, too early in the collaboration
Start Year 2023
Description Collaborator visit to Kyoto University, Japan 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A visit to Kyoto, Japan to discuss collaborations between researchers in Kyoto, and researchers in Leeds. Since the visit, research has started on a joint collaboration. My input is on pancreatic cancer spheroids.
Year(s) Of Engagement Activity 2022
Description Leeds Centre for Disease Models Annual Meeting 2023 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited speakers at the Leeds Centre for Disease Models in which I presented a 20 minute talk on the pancreatic disease models I'm developing as part of this funding. This lead to questions and collaboration talks with academics from different faculties
Year(s) Of Engagement Activity 2023