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Matrix during cancer progression

Periodic Reporting for period 3 - MATRICAN (Matrix during cancer progression)

Reporting period: 2019-09-01 to 2021-02-28

1 in 3 people will develop cancer in their lifetime, and over 90% of cancer patients die because their cancer has spread through the body - a process called metastasis. All organs and tumours are comprised of a mixture of cells held within a structural scaffold known as the extracellular matrix (ECM). We and others have shown that targeting the ECM scaffold can disrupt tumour growth and metastasis, and also enhance the killing potential of chemotherapy. We therefore believe that through understanding the precise composition and structure of the ECM, we will be able to know how to dismantle tumours.

We have developed a method to isolate ECM scaffolds from organs and tumours such that the 3 dimensional architecture is preserved. We can analyse these ECM scaffolds to know what components they are comprised of and to visualise their structure. The aim of the project is to analyse ECM scaffolds isolated from healthy and cancer-bearing organs to identify potential opportunities for therapeutic intervention to block cancer progression. The overall objectives are to characterise how the ECM scaffold is altered between healthy and cancer states, to test new therapeutic targeting strategies and to study the underlying biology to know how the ECM scaffold can control cell behaviour.

This project is important to society because it studies fundamental biology providing new information on how the body function and how cancer is regulated, and also by developing new therapeutic strategies to block cancer progression that could be translated into the clinic to decrease cancer patient suffering and increase cancer patient survival.
We published our new method to isolate native ECM scaffolds from organs and tumours (Mayorca et al, 2017, Nature Medicine). We expanded this method to decellularise 33 organs and stain for 35 ECM proteins. This study has just been published in Nature Protocols. We are working on a follow-up study where we re-populate the ECM scaffolds with cells to study how they behave in native ECM. We aim to submit this manuscript next month. We have also developed a method to decellularise human tissue, and intend to publish the method and our findings early next year.

We had previously collected information on ECM scaffolds from a very basic model of breast cancer. We identified several targets to investigate and have found that these indeed do play a major role in regulating cancer progression. We are finalising four manuscripts to publish these findings. We have now collected ECM scaffolds from a more complex model of cancer that more closely recapitulate human disease. We have analysed these samples by mass spectrometry and are currently selecting which targets to follow up.

In parallel, we have investigated signalling in pancreatic cancer tumours and identified a kinase inhibitor effective against tumour progression. This study was submitted and is currently under revision.

Given the low throughput nature of the bioreactor studies and the challenges with acquiring quantitative data, we have developed in we have developed in vitro methods to study cell response to ECM proteins. These studies are ongoing.
Our studies of cancer cell behaviour within the ECM scaffolds is state of the art. Our ability to decellularise human tissue is also state of the art. We expect to gain much information on how ECM scaffolds regulate cell behaviour in healthy and cancer contexts. We aim to use our analysis of the ECM scaffolds collected from the closer-to-clinic models to test new ways to disrupt cancer progression. We will also confirm our findings using human patient samples. Our studies of cell behaviour in response to ECM components are state of the art, and will provide profound insight into fundamental cell behaviour.
Mouse lung bearing metastatic tumour. Organ decellularised using ISDoT (Mayorca et al, 2017)