MICA: PANC-AID: Engineering a novel dynamic pancreatic cancer organoid model (MICA)

Lead Research Organisation: University College London
Department Name: Targeted Intervention

Abstract

Pancreatic cancer is a serious disease of the pancreas with very poor prognosis and low survival rate (<8% of patients survive the disease). Furthermore, as oppose to other cancers where we have seen significant improvement of survival due to novel treatment developments, there has been hardly any improvement over the last decades for pancreatic cancer. A key aspect that leads to the progression of the disease is the so-called tissue (tumour) microenvironment (TME), which is essentially a cocktail of cells and biomolecules which interact with the tumour, making it resistant to treatment and helping it metastasise.

Typically, therapies for pancreatic cancer are tested on animal models or on tumour cells cultured in 2D static conditions. While the complexity associated with animal studies improves the disease insight, they are expensive, complex, difficult to reproduce and many times unrepresentative. 2D single cell cultures are easy to use, reproducible and cost-efficient, however, they are unable to reproduce topologically, mechanically, biologically and biochemically the complex TME. More recently, 3D spheroid type ('tissue-spheres') cultures from human and mouse pancreatic cancer represent the state-of-the- art as they can be cultured for longer than 2D systems, they are suitable for drug screening. These can be established from small biopsy specimens, so in principle can be used to identify some tumour characteristics of individual patients. However, the self-organising nature of spheroids and the lack of mechanical and biochemical integrity limits the tuneability of the environment, therefore reducing the versatility of these models. An in vitro system with robust control of the biophysical, biochemical and biomechanical environment is currently lacking and would benefit the patients and the research community substantially as there is clear evidence in the state of the art that the biomechanical and biophysical environment can affect the disease progression, metastasis and response to treatment.

The aim of our project is to develop a high fidelity pancreatic cancer model, which will enable patient & disease specific treatment optimization via robust control of various biochemical, biomechanical and biophysical features of the TME. More specifically, tailoring in a controlled manner parameters of the tumour microenvironment like extracellular matrix composition, stiffness (at levels that realistically occur in PDAC in vivo), interstitial flow rates (mimicking high or low vascularisation or avascular tumours), vessel sizes or fibrotic levels (mimicking dense or less dense fibrotic reaction) will enable the conduction of long term fundamental studies unravelling the interaction of each of those parameters with different cells of the tumour microenvironment. Underpinning such interactions at multiple levels, i.e., genetic, metabolic, will enable a better understanding of the evolution of the disease as well as the role of different TME configurations on driving signaling pathways for migration and metastasis. Furthermore, such a robust, tuneable, representative model for pancreatic cancer will help improve the success rate of emerging therapies and constitute a platform for personalised medicine.

Technical Summary

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease with 91% of patents dying within five years from diagnosis. The disappointing statistics on pancreatic cancer treatment outputs are partly due to the complex tumour microenvironment (TME) which induces resistance to treatment. Therefore, ensuring accurate mimicry of the TME in pancreatic cancer studies and treatment screening is of high importance.
The aim of our project is to develop a high fidelity in vitro pancreatic cancer model, which will enable patient & disease specific treatment optimisation.
For the accomplishment of our aim we will use as a basis our static developed 3D pancreatic cancer multicellular model (consisting pancreatic tumour cells, stellate cells and endothelial cells) which is based on a highly porous polyurethane scaffolding system and further advance it with tuneable features of the TME, i.e., different internal structure/porosity, various extracellular matrix protein compositions, different cell rations to tune fibrosis which is a hallmark of PDAC and interstitial flow (to mimic different tissue vascular levels and shear stress).
Our preliminary work and existing publications on this direction shows that all cell types are viable in the polymer scaffold for a month in culture, which is extremely encouraging especially for endothelial cells which cannot remain live for so long in a 3D spheroid type organisation. Also, our model captures the fibrotic reaction around the pancreatic cancer cells. Furthermore, the versatility of the synthetic scaffold allows to recapitulate and test multiple critical aspects of the TME including extracellular matrix, stiffness, tissue porosity, diffusion of oxygen, nutrients, metabolites and distribution of the vascularisation.
The ability to reproducibly represent & control different biophysical, biochemical and biomechanical features of tumor microenvironments in vitro from presents a clear advantage, compared to current in vitro approaches.

Publications

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