ArticleCancer research2011
Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2.
Article in Cancer research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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Who cites it
101 citing papers in PubMed, 179 citations in OpenAlex.
- CAF-derived PTGDS drives pancreatic cancer neuroendocrine differentiation and chemoresistance via PAQR9-MAPK.Oncogenesis · 2026Article
- Novel anti-tumor strategies: targeting the crosstalk between cancer stem cells and cancer-associated fibroblasts to resist drug resistance.Cancer drug resistance (Alhambra, Calif.) · 2026Review
- A 3D Bioprinted Pancreatic Cancer Model Using Collagen-Gelatin Methacrylamide-Alginate Bioinks to Mimic the Desmoplastic Microenvironment.Biomacromolecules · 2025Article
- The Duality of Collagens in Metastases of Solid Tumors.International journal of molecular sciences · 2025Review
- Sequential drug release system: Targeting the tumor ECM for enhanced chemotherapy efficacy.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Novel De NovoInternational journal of molecular sciences · 2025Article
- Pancreatic cancer-derived extracellular vesicles enhance chemoresistance by delivering KRASMolecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Integrative analysis regarding the correlation between collagen-related genes and prostate cancer.BMC cancer · 2024Article
- A stumbling block in pancreatic cancer treatment: drug resistance signaling networks.Frontiers in cell and developmental biology · 2024Review
- LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance.International journal of biological sciences · 2024Review
- Exploring the Role of Desmoplastic Physical Stroma in Pancreatic Cancer Progression Using a Three-Dimensional Collagen Matrix Model.Bioengineering (Basel, Switzerland) · 2023Article
- Beyond matrix stiffness: targeting force-induced cancer drug resistance.Trends in cancer · 2023Review
- microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer.Cancers · 2023Review
- Pancreatic stellate cell-induced gemcitabine resistance in pancreatic cancer is associated with LDHA- and MCT4-mediated enhanced glycolysis.Cancer cell international · 2023Article
- Review
- Context Matters: Response Heterogeneity to Collagen-Targeting Approaches in Desmoplastic Cancers.Cancers · 2022Review
- Matrix stiffening and acquired resistance to chemotherapy: concepts and clinical significance.British journal of cancer · 2022Review
- Expression and Clinical Significance of High-Mobility Group AT-hook 2 (HMGA2) in Osteosarcoma.Orthopaedic surgery · 2022Article
- Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma.Cancers · 2022Review
- A new era: tumor microenvironment in chemoresistance of pancreatic cancer.Journal of cancer science and clinical therapeutics · 2022Article
41 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP-dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP in the collagen microenvironment increases ERK1/2 phosphorylation and HMGA2 expression, and thereby further attenuates gemcitabine-induced checkpoint arrest. MT1-MMP also allows PDAC cells to continue to proliferate in the presence of gemcitabine in a xenograft mouse model. Clinically, human tumors with increased MT1-MMP show increased HMGA2 expression. Overall, our data show that collagen upregulation of MT1-MMP contributes to gemcitabine resistance in vitro and in a xenograft mouse model, and suggest that targeting MT1-MMP could be a novel approach to sensitize pancreatic tumors to gemcitabine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.