Pancreatic ductal adenocarcinoma (PDAC) is the most common and deadly form of pancreatic cancer. The overall 5-year survival rate for patients with PDAC was only 7.1%.
All cancers are different. A unique feature of PDAC is the extensive intratumoral tumor connective tissue or fibrous connective tissue, which results from infiltration of the tumor mass by fibroblasts and their secreted extracellular matrix. The main component of the matrix is collagen type I, or Col 1, a protein widely used in the body to form the basic structure of bone, skin, blood vessels, and connective tissue.
The effect of Col 1 on PDAC development and its response to therapy has been a subject of intense debate among researchers, with some arguing that Col 1 promotes tumor growth and spread, while others believe it limits tumor growth and protects cancer cells from immunity attack.
In a new study published October 5, 2022, nature, co-first author Hua Su, Ph.D., and a postdoc in senior author Michael Karin’s lab. Fei Yang, Ph.D., Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine and scientist in collaboration with Beicheng Sun, Ph.D., Nanjing University School of Medicine, by demonstrating 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, which is cleaved by matrix metalloproteinases (enzymes that break down matrix proteins, such as collagen), stimulates tumor growth, while intact, uncleaved Col 1 inhibits tumor growth.
“Furthermore,” Su said, “cleaved Col 1 activates a signaling pathway that stimulates energy production in pancreatic cancer cells by binding to a receptor protein called DDR1. Uncleaved Col 1 inhibits this pathway by inducing the degradation of DDR1.”
The study was performed using a mouse model and a novel culture system in which PDAC cells were plated on extracellular matrix containing cleaved or uncleaved Col 1 .
The findings have important clinical implications, the authors say.
The relative amount of cut versus uncut Col 1 in human PDAC stroma or connective tissue strongly affects patient survival after surgical resection. Patients whose tumors were rich in cleaved Col 1 and whose cancer cells expressed high levels of DDR1 fared poorly, with most dying of their disease within two years of surgery.
This patient group represented 75% of the 106 patients analyzed for the study, using cancer specimens provided by Beicheng Sun, MD, of the Drum Tower Hospital affiliated to Nanjing University School of Medicine, China, and colleagues.
In contrast, patients whose 25% of tumors contained predominantly uncut Col 1 and had low levels of DDR1 expression had a much better survival outlook.
“This work is important because it provides an easy way to stratify patients and suggests that patients with high levels of cleaved Col 1 and DDR1 expression require more aggressive postoperative treatment,” Karin said.
“It also provides evidence that the most effective treatment for this group of patients should include DDR1 inhibitors or key components of its signaling pathway, whose activation leads to increased mitochondria (the cell’s power plant) in PDAC cells.”
In addition to DDR1 inhibitors, which are not yet in clinical practice, the authors propose another treatment option that has shown efficacy in mice with PDAC, the FDA-approved antibiotic tigecycline, which inhibits mitochondrial protein synthesis And reduce the energy-producing PDAC mitochondria.
Co-authors include: Rao Fu, Nanjing University School of Medicine; Brittney Trinh, Nina Sun, Junlai Liu, Jacopo Baglieri, Nachanok Sinchai, Jeremy Siruno, Stephen Dozier, Ajay Nair, Aveline Filliol, Sara Brin Rosenthal, Jennifer Santini, Anthony Molina, Robert F . Schwabe, Andrew M. Lowy and David Brenner, all at UC San Diego; and Avi Kumar and Christian M. Metallo of the Salk Institute.