Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome
Open accessAbstract
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.
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Collagen acts as a signaling molecule by activating discoidin domain receptor signaling in PDAC pathology.
“Collagen also acts as a signaling molecule, activating discoidin domain receptor signaling that shape multiple roles in PDAC pathology168–171”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [169]
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- Authors
- Su, H., Yang, F., Fu, R., Trinh, B., Sun, N., Liu, J., Kumar, A., Baglieri, J., Siruno, J., Le, M., Li, Y., Dozier, S., Nair, A., Filliol, A., Sinchai, N., Rosenthal, S. B., Santini, J., Metallo, C. M., Molina, A., Schwabe, R. F., Lowy, A. M., Brenner, D. A., Sun, B., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Nanjing Drum Tower Hospital (CN)
- Salk Institute for Biological Studies (US)
- Columbia University (US)
- Corresponding author
- Sun, Beicheng
- Karin, Michael
- ORCID
- Venue
- Nature
- Published
- 2022-10-05
- Volume
- 610
- Issue
- 7931
- Pages
- 366-372
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9588640
- OpenAlex
- W4302010997
- Cited by
- 221
- References
- 37
- Citations by year
- 2026: 42 · 2025: 56 · 2024: 87 · 2023: 32 · 2022: 4
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Update notices
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (U01AA027681, P50AA011999)
- National Cancer Institute (R01CA234245, R01CA218254, R01CA190844, P30CA023100, R01CA211794, R01CA262424, P30CA014195, U01CA274295)
- National Institute of Allergy and Infectious Diseases (R37AI043477)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK132710, P01DK098108)
- National Institute of Neurological Disorders and Stroke (P30NS047101)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- pancreatic ductal adenocarcinoma, type I collagen, collagen degradation, DDR1, NF-κB, Nrf2, p62, mitochondrial biogenesis, tumor stroma, macropinocytosis, cancer-associated fibroblasts, metastasis, patient survival, tumor growth
- MeSH terms
- Discoidin Domain Receptor 1, Animals, Mitochondria, Signal Transduction, Survival Rate, NF-kappa B, Matrix Metalloproteinases, Carcinoma, Pancreatic Ductal, Collagen Type I, Cell Line, Tumor, NF-E2-Related Factor 2, Mice
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