2. Academic Validation
  3. Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome

Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome

  • Nature. 2022 Oct;610(7931):366-372. doi: 10.1038/s41586-022-05169-z.
Hua Su  # 1,  Fei Yang  # 2,  Rao Fu 2,  Brittney Trinh 1,  Nina Sun 3,  Junlai Liu 1,  Avi Kumar 4,  Jacopo Baglieri 3,  Jeremy Siruno 1,  Michelle Le 1,  Yuhan Li 1,  Stephen Dozier 3,  Ajay Nair 5,  Aveline Filliol 5,  Nachanok Sinchai 1,  Sara Brin Rosenthal 6,  Jennifer Santini 7,  Christian M Metallo 4,  Anthony Molina 3,  Robert F Schwabe 5,  Andrew M Lowy 8,  David Brenner 3,  Beicheng Sun 9 10,  Michael Karin 11
Affiliations

Affiliations

  • 1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 2 Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 3 Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 4 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • 5 Department of Medicine, Columbia University, New York, NY, USA.
  • 6 Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 7 UCSD School of Medicine Microscopy Core, University of California San Diego, La Jolla, CA, USA.
  • 8 Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 9 Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. sunbc@nju.edu.cn.
  • 10 Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China. sunbc@nju.edu.cn.
  • 11 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA. karinoffice@health.ucsd.edu.
  • # Contributed equally.
PMID: 36198801 DOI: 10.1038/s41586-022-05169-z
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive Cancer that frequently progresses and spreads by metastasis to the liver1. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support2,3 or restrain the progression of PDAC and may impede blood supply and nutrient availability4. 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.

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