A promising new molecular target for pancreatic cancer

Researchers at the Garvan Institute of Medical Research have identified a potential new therapeutic target for pancreatic cancer. Published in Science Advances, their research showed that blocking the molecule nidogen-2 enhanced the effectiveness of chemotherapy and reduced the cancer’s spread in mouse models.

Pancreatic cancer is an aggressive disease with a five-year survival rate of just 12%, largely because it is often diagnosed at an advanced stage and can resist conventional treatment options. To identify new therapeutic targets, the Garvan researchers used a technique called tissue decellularisation, which removes all the cells from a tumour sample but retains its scaffolding components, known as the extracellular matrix.

By comparing the scaffolds of mouse tumours that metastasise with those that don’t, the team discovered that the molecule nidogen-2 was elevated in the matrix of more aggressive tumours as the disease progressed. Using CRISPR gene editing, they depleted nidogen-2 levels in pancreatic tumours to observe its effect on the cancer’s growth and treatment response in mouse models in real time, using state-of-the-art intravital imaging at Garvan’s ACRF INCITe Centre.

“The results were striking,” said co-first author Dr Brooke Pereira, Senior Research Officer at Garvan. “When we reduced nidogen-2 in pancreatic tumours, we saw a decrease in matrix density, smaller tumours and an improvement in blood vessel structure.

“Tumours with less nidogen-2 had blood vessels that were more open — they were wider and more evenly distributed compared to the collapsed and chaotic vessels usually seen in pancreatic cancer. This caught our attention, because you need functional blood vessels to deliver chemotherapy drugs into the tumour effectively — it’s one of the biggest challenges in treating pancreatic cancer. By targeting nidogen-2, we were able to normalise the tumour blood vessels.”

When researchers administered chemotherapy in their models with reduced levels of nidogen-2, they found that the treatment could more effectively reach the whole tumour. Nidogen-2 reduction also led to significantly less metastatic spread to the liver in mouse models and improved survival compared to controls.

“This dual effect of enhancing chemotherapy while also reducing metastasis is really exciting,” said co-senior author Associate Professor Thomas Cox, Head of Garvan’s Matrix and Metastasis Lab. “It suggests that targeting nidogen-2 could be a promising new approach for pancreatic cancer.”

“Our novel approach — removing all the cells from the tumour tissue to leave behind the scaffolding of the tumour — allowed us to identify molecules like nidogen-2 that weren’t previously on our radar,” added co-senior author Professor Paul Timpson, Head of Garvan’s Invasion and Metastasis Lab. “It’s a powerful way to uncover new clinical targets in the tumour microenvironment, which for decades was overlooked but we now know plays a critical role in cancer progression.”

The researchers are now working on developing clinical approaches to target nidogen-2, such as blocking antibodies that bind to it, which could be combined with existing chemotherapy regimens to allow the drugs to better penetrate the tumour and kill cancer cells. In future, their approach may also be combined with immunotherapy to further improve outcomes for pancreatic cancer patients.

“Pancreatic cancer has seen minimal improvement in survival for decades, so we urgently need new tactics,” Timpson said. “We believe targeting the tumour scaffolding through nidogen-2 could be a vital step forward in improving treatment of this aggressive disease.”

Image caption: Microscopic view inside a mouse model of a pancreatic cancer tumour. The colours indicate different components: red for blood vessels, green for tumour cells and purple for collagen, the connective tissue making therapy penetration challenging.