Garvan Breakthrough December 2019

S L O W I N G

the spread of pancreatic cancer

An international team led by Garvan researchers has revealed how aggressive pancreatic cancer cells change their environment to enable easy passage to other parts of the body (or metastasis) – the main cause of pancreatic cancer related death.

Using mouse models, the team extracted fibroblasts – cells that produce most of the matrix – from spreading and non-spreading pancreatic tumours. By mixing these different fibroblasts with cancer cells, the researchers found that remarkably, cancer cells from a non-spreading tumour began to spread when mixed with fibroblasts from a spreading tumour. Using state-of-the-art mass spectrometry techniques, the researchers discovered several molecules that the fibroblasts from metastatic tumours produced at significantly higher levels than the fibroblasts from non-metastatic tumours. “What we discovered is a previously unknown set of matrix molecules that aggressive pancreatic cancer cells use to shape the tissue around them, which prevents chemotherapy from working and allows the cancer cells to spread around the body,” explains Dr Cox. Using gene-editing techniques, the researchers reduced the levels of one of the molecules called perlecan in mouse models of aggressive metastatic pancreatic cancer. Through advanced live imaging techniques, the researchers tracked individual cancer cells and revealed that lowering the levels of perlecan not only reduced the spread of cancer cells, but that tumours also responded better to chemotherapy. The researchers hope that specifically targeting aggressive fibroblasts in patients harbouring precise genetic changes will allow them to make pancreatic cancer more susceptible to currently approved treatments. An untapped resource

The researchers discovered that some pancreatic tumours produce more of a molecule called ‘perlecan’ to remodel the environment around them, which helps cancer cells spread more easily to other parts of the body, and also protects them against chemotherapy.

A/Prof Paul Timpson and Dr Thomas Cox

In a mouse model, the researchers showed that lowering the levels of perlecan resulted in a reduction in the spread of pancreatic cancer and improved response to chemotherapy.

Led by Associate Professor Paul Timpson, Head of the Invasion and Metastasis laboratory, and Dr Thomas Cox, leader of the Matrix and Metastasis group, the research may provide a promising new path to more effective treatment options for individuals with pancreatic cancer, as well as other cancers.

A spotlight on the tumour matrix

Pancreatic cancer is one of the most lethal forms of cancer, with a five-year survival of ~9% in Australia. In its early stages, pancreatic cancers often show no obvious signs or symptoms and by the time a cancer is diagnosed, it has often begun to spread outside the pancreas. In their study, the researchers compared the tissue around tumour cells in both metastatic (spreading) and non-metastatic (non-spreading) pancreatic cancers. This tissue – known as the ‘matrix’ – acts like a glue that holds different cells in an organ or in a tumour together.

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