Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix
Open accessAbstract
Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies.
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Depletion of stromal fibroblasts through hedgehog inhibition, epithelial sonic hedgehog deletion, stromal ablation, or LOXL2 inhibition increases tumor access to blood supply and facilitates metastasis, with deleterious consequences.
“depletion of stromal fibroblasts through hedgehog inhibition, epithelial sonic hedgehog deletion, stromal ablation, or inhibition of lysyl oxidase like-2 increases tumor access to the blood supply and facilitates metastasis, having deleterious consequences on natural history of the disease159–162”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [161]
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- Authors
- Jiang, H., Torphy, R. J., Steiger, K., Hongo, H., Ritchie, A. J., Kriegsmann, M., Horst, D., Umetsu, S. E., Joseph, N. M., McGregor, K., Pishvaian, M. J., Blais, E. M., Lu, B., Li, M., Hollingsworth, M., Stashko, C., Volmar, K., Yeh, J. J., Weaver, V. M., Wang, Z. J., Tempero, M. A., Weichert, W., & Collisson, E. A.
- Affiliations
- University of California, San Francisco (US)
- University of Colorado Anschutz (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University Hospital Heidelberg (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Foundation Medicine (United States) (US)
- Johns Hopkins University (US)
- Bristol-Myers Squibb (United States) (US)
- University of Nebraska Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Collisson, Eric A.
- ORCID
- Jiang, Honglin
- Torphy, Robert J.
- Steiger, Katja
- Hongo, Henry
- Kriegsmann, Mark
- Horst, David
- Umetsu, Sarah E.
- Joseph, Nancy M.
- McGregor, Kimberly
- Pishvaian, Michael J.
- Blais, Edik M.
- Lu, Brian
- Li, Mingyu
- Hollingsworth, Michael
- Stashko, Connor
- Yeh, Jen Jen
- Weaver, Valerie M.
- Wang, Zhen J.
- Tempero, Margaret A.
- Weichert, Wilko
- Collisson, Eric A.
- Venue
- Journal of Clinical Investigation
- Published
- 2020-08-04
- Volume
- 130
- Issue
- 9
- Pages
- 4704-4709
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7456216
- OpenAlex
- W3047538947
- Cited by
- 127
- References
- 30
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 14 · 2023: 25 · 2022: 31 · 2021: 24 · 2020: 3
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- UNC Libraries
- Funders
- National Cancer Institute (R01CA178015, R01CA227807, R01CA222862)
- National Institutes of Health (CA193650, CA199064, NCATS Colorado CTSA TL1 TR002533)
- Deutsche Forschungsgemeinschaft (329628492)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- pancreatic ductal adenocarcinoma, tumor stroma, desmoplasia, extracellular matrix, LOXL2, liver metastasis, tumor cellularity, tissue stiffness, tumor progression, overall survival, syngeneic mouse model
- MeSH terms
- Aged, Animals, Extracellular Matrix, Female, Humans, Male, Mice, Transgenic, Middle Aged, Pancreatic Neoplasms, Stromal Cells, Carcinoma, Pancreatic Ductal, Mice, Tumor Microenvironment
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