Pancreatic ductal adenocarcinoma (PDAC) is the most typical and most deadly type of pancreatic most cancers. The total 5-year survival for sufferers with PDAC is simply 7.1 p.c.
All cancers are totally different. A singular characteristic of PDAC is in depth tumor desmoplasia or fibrous connective tissue throughout the tumor, which is attributable to infiltration of the tumor mass by fibroblasts and the extracellular matrix they secrete. The fundamental element of the matrix is sort I collagen or Col 1, a protein broadly used within the physique to type the essential construction of bone, pores and skin, blood vessels and connective tissues.
The impact of Col 1 on PDAC improvement and its response to remedy has been a matter of intense debate amongst researchers, with some arguing that Col 1 promotes tumor development and unfold and others contending that it restricts tumor development and protects the most cancers cells from immune assault.
In a new examine, printed October 5, 2022, in Nature, co-first authors Hua Su, PhD, a postdoctoral fellow within the lab of senior creator 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 controversy by exhibiting that it is not the quantity of Col 1 current within the tumor that issues, however its high quality and nature.
Specifically, they report that Col 1 that has been cleaved by matrix metalloproteases (enzymes that break down matrix proteins, similar to collagen) stimulates tumor development whereas intact and non-cleaved Col 1 inhibits tumor development.
“Moreover,” stated 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 analysis was carried out utilizing mice fashions and a novel tradition system through which PDAC cells have been plated on extracellular matrix that contained both cleaved or non-cleaved Col 1.
The authors stated the findings have necessary scientific implications.
The relative quantities of cleaved versus non-cleaved Col 1 within the human PDAC stroma or connective tissue strongly have an effect on affected person survival after surgical resection. Patients whose tumors have been enriched in cleaved Col 1 and whose cancerous cells expressed excessive ranges of DDR1 fared poorly, with most succumbing to their illness inside two years of surgical procedure.
This affected person group represented 75 p.c of the 106 sufferers analyzed as half of the examine, utilizing most cancers specimens offered by Beicheng Sun, MD, PhD, and colleagues on the Affiliated Drum Tower Hospital of Nanjing University Medical School in China.
In distinction, the 25 p.c of sufferers whose tumors primarily contained non-cleaved Col 1 with low ranges of DDR1 expression skilled significantly 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,” stated 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 signaling pathway whose activation results in increased number of mitochondria, the cellular power plants, in PDAC cells.”
In addition to DDR1 inhibitors not but in scientific apply, the authors prompt one other therapy choice, proven to be efficient in PDAC-bearing mice, is the U.S. Food and Drug Administration accepted antibiotic tigecycline, which might inhibit mitochondrial protein synthesis and reduce the quantity of energy-producing PDAC mitochondria.
Co-authors embody: Rao Fu, Nanjing University Medical School; 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, Salk Institute.
