Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome

• Published in: Nature (London) 2022-10, Vol.610 (7931), p.366-372
• Main Authors: Su, Hua, Yang, Fei, Fu, Rao, Trinh, Brittney, Sun, Nina, Liu, Junlai, Kumar, Avi, Baglieri, Jacopo, Siruno, Jeremy, Le, Michelle, Li, Yuhan, Dozier, Stephen, Nair, Ajay, Filliol, Aveline, Sinchai, Nachanok, Rosenthal, Sara Brin, Santini, Jennifer, Metallo, Christian M., Molina, Anthony, Schwabe, Robert F., Lowy, Andrew M., Brenner, David, Sun, Beicheng, Karin, Michael
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 14/1; 14/19; 38/1; 38/109; 38/15; 38/39; 38/77; 38/91; 631/67/2327; 631/67/327; 631/80/86/2369; 692/699/67/2327; Ablation; Adenocarcinoma; Amino acids; Animals; Bioenergetics; Biosynthesis; Cancer; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Collagen; Collagen (type I); Collagen Type I - metabolism; Discoidin Domain Receptor 1 - metabolism; Extracellular matrix; Fibroblasts; Humanities and Social Sciences; Liver cancer; Matrix metalloproteinase; Matrix Metalloproteinases - metabolism; Metabolism; Metalloproteinase; Metastases; Metastasis; Mice; Mitochondria; Mitochondria - metabolism; multidisciplinary; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB protein; Nutrient availability; Nutrients; Pancreatic cancer; Patients; Science; Science (multidisciplinary); Signal Transduction; Signaling; Stroma; Survival; Survival Rate; Tumorigenesis; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05169-z

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver 1 . Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support 2 , 3 or restrain the progression of PDAC and may impede blood supply and nutrient availability 4 . The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)–NF-κB–p62–NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I–DDR1–NF-κB–NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities. Cleaved and intact type I collagen have different effects on pancreatic ductal adenocarcinoma (PDAC), and remodelling of type I collagen—mediated through DDR1 signalling—is a prognostic indicator for the survival of patients with PDAC.