Survival is a mixed matter for deadliest of pancreatic cancers

Pancreatic ductal adenocarcinoma (PDAC) is the most common and most lethal form of pancreatic cancer. The overall 5-year survival for patients with PDAC is just 7.1 percent.

All cancers are different. A unique feature of PDAC is extensive tumor desmoplasia or fibrous connective tissue within the tumor, which is caused by infiltration of the tumor mass by fibroblasts and the extracellular matrix they secrete. The main component of the matrix is 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 tumor growth and spread and others contending that it restricts tumor 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 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 tumor that matters, but its quality and nature.

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

“Moreover,” said Su, “cleaved Col 1 activates a signaling 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 mice models and a novel culture system in which PDAC cells were plated on extracellular matrix that contained either cleaved or non-cleaved Col 1.

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