Seeing is believing: Mapping and targeting the extracellular matrix
In 2017 Prof Paul Timpson and A/Prof Thomas Cox received an Avner Accelerator Grant to map and target the extracellular matrix of pancreatic cancer cells. The team have recently finished their project and provided us with an update of their work.
A bit of background
A cancer cell’s surroundings significantly impact on disease progression. The team has devised a new way to dissolve cells from tumours, leaving behind the delicate 3D-architecture of the matrix allowing them to study and tap into the vast and currently unexplored reservoir of anti-cancer matrix targets in this disease.
The vast majority of cancer studies place an emphasis on studying the behaviour and signalling pathways of tumour cells. Despite this, pancreatic tumours are strongly influenced by the “microenvironment” that tumour cells reside in. Pancreatic tumours are often characterised by high levels of fibrosis, where excess levels of extracellular matrix (ECM) are deposited. Pancreatic cancer development, local spread, distant metastasis, and treatment resistance are strongly influenced by this fibrotic tissue and can be co-targeted together with tumour cell-centric therapies. The ECM therefore presents a vast, unexplored repository of anti-cancer targets, which we have been able to investigate with the generous support of PanKind's funding.
Using state-of-the-art tissue decellularization (ECM enrichment) and advanced imaging approaches we have mapped the distribution, organisation, and assembly of the fibrotic tissue in pancreatic cancer to identify new ECM targets specific to pancreatic cancer progression. Furthermore, our multidisciplinary team of cancer researchers, bioengineers, pathologists, surgeons, and clinicians have created the first national and international comprehensive human pancreatic cancer ECM database, known as the Australian Pancreatic Cancer Matrix Atlas (APMA). The overarching goal of APMA is to facilitate the translation of anti-fibrotic therapies as a mainstay in our emerging multimodal armoury against pancreatic cancer. This program involved establishing a pipeline in collaboration with the Australian Pancreatic Cancer Genomic Initiative (APGI) to decellularize, process and assess fresh patient tumours within one hour of receiving the specimen from the surgery suite. These tumours are also then propagated in host animals, creating a living biobank of pancreatic specimens to rapidly test ECM manipulations (with or without) standard-of-care treatment such as chemotherapy. This comprehensive biobanking resource aligns with the APGI core mission, providing a holistic approach to targeting pancreatic cancer via the cancer cells as well as their fibrotic microenvironment.
Overall, PanKind, The Australian Pancreatic Cancer Foundation has allowed us to make significant inroads to reduce the devastating burden of this insidious disease using our innovative dual targeting approach: targeting the tumour as well as the surrounding ECM. Future work will include rapidly translating our findings to the clinic, presenting an opportunity to markedly improve the grim outcomes currently observed in pancreatic cancer.
Written by Prof Paul Timpson, Garvan Institute of Medical Research.