The most prevalent and fatal kind of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). PDAC patients have a 5-year survival rate of only 7.1 per cent.

All cancers are different. A unique feature of PDAC is extensive tumour desmoplasia or fibrous connective tissue within the tumour, which is caused by infiltration of the tumour mass by fibroblasts and the extracellular matrix they secrete.

The main component of the matrix is a type I collagen or Col 1, a protein broadly used in the body to form the basic structure of bone, skin, blood vessels and connective tissues.

The effect of Col 1 on PDAC development and its response to therapy has been a matter of intense debate among researchers, with some arguing that Col 1 promotes tumour growth and spread and others contending that it restricts tumour growth and protects the cancer cells from immune attack.

In a new study, published October 5, 2022, in Nature, co-first authors Hua Su, PhD, a postdoctoral fellow in the lab of senior author Michael Karin. PhD, distinguished professor of Pharmacology and Pathology at the University of California San Diego School of Medicine, and Fei Yang, PhD, a scientist working with Beicheng Sun, MD, PhD, at Nanjing University School of Medicine, settle the debate by showing that it is not the amount of Col 1 present in the tumour that matters, but it's quality and nature. 

Specifically, they report that Col 1 which has been cleaved by matrix metalloproteases (enzymes that break down matrix proteins, such as collagen) stimulates tumour growth while intact and non-cleaved Col 1 inhibits tumour growth.

"Moreover," said Su, "Cleaved Col 1 activates a signalling pathway that stimulates energy production in pancreatic cancer cells by binding to a receptor protein called DDR1. Non-cleaved Col 1 inhibits this pathway by inducing the degradation of DDR1."

The research was conducted using experimental models and a novel culture system in which PDAC cells were plated on an extracellular matrix that contained either cleaved or non-cleaved Col 1. The authors said the findings have important clinical implications. 

The relative amounts of cleaved versus non-cleaved Col 1 in the human PDAC stroma or connective tissue strongly affect patient survival after surgical resection. Patients whose tumours were enriched in cleaved Col 1 and whose cancerous cells expressed high levels of DDR1 fared poorly, with most succumbing to their disease within two years of surgery.

This patient group represented 75 per cent of the 106 patients analysed as part of the study, using cancer specimens provided by Beicheng Sun, MD, PhD, and colleagues at the Affiliated Drum Tower Hospital of Nanjing University Medical School in China.

In contrast, 25 per cent of patients whose tumours mainly contained non-cleaved Col 1 with low levels of DDR1 expression experienced much better survival prospects.

"This work is important because it provides a simple way for patient stratification and suggests that patients with high levels of cleaved Col 1 and DDR1 expression need more aggressive post-surgery treatments," said Karin.

"It also provides evidence that the most effective therapy for this group of patients should include inhibitors of DDR1 or key components of its signalling pathway whose activation results in an increased number of mitochondria, the cellular power plants, in PDAC cells."