The DOI matches its Crossref record; 59 of the 61 references it cites were found in a registry or an index.
Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma
Open accessPublished version of a preprint
Abstract
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473–85. ©2017 AACR.
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“PDAC cells produce “tonic” (low) levels of a distinct oncogenic homo-trimeric collagen that binds to α3β1 integrin, thereby mediating immune suppression and reprogramming the tumor-associated microbiome167”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [167]
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1 retracted
DDR1 Receptor Tyrosine Kinase Promotes Prosurvival Pathway through Notch1 Activation
Kim, H.-G., Hwang, S.-Y., Aaronson, S. A., Mandinova, A., & Lee, S. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.236612 · Cited by 94 · cited 1×
“DDR1 inhibition has also been shown to reduce tumorigenicity in multiple tumor models (23, 25, 51, 52).”
BackgroundRetractedKalluri, R., & Zeisberg, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1877 · Cited by 4,538 · cited 1×
“Collagen is expressed in PDA by stromal cells, mainly fibroblasts, with a relatively minor but functionally relevant contribution by tumor cells (18, 19).”
BackgroundSomatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681 · cited 1×
“Dasatinib in particular has demonstrated promising therapeutic efficacy in lung cancer cells (57) and squamous cell carcinoma patients (58) harboring gain-of-function DDR2 mutations.”
BackgroundHingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609
Collagen density promotes mammary tumor initiation and progression
Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C., White, J. G., & Keely, P. J. (2008) · BMC Medicine · doi:10.1186/1741-7015-6-11 · Cited by 1,394
Hoff, D. D. V., Ramanathan, R. K., Borad, M. J., Laheru, D. A., Smith, L. S., Wood, T. E., Korn, R. L., Desai, N. P., Trieu, V. N., Iglesias, J. L. M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.5742 · Cited by 1,040 · cited 1×
“In addition, it was reported that the restoration of SPARC expression enhanced radiosensitivity and chemosensitivity in preclinical models of colon cancer (45) and that SPARC expression enhanced chemoresponse in cancer patients (46, 47).”
BackgroundChauhan, V. P., Martin, J. D., Liu, H., Lacorre, D. A., Jain, S. R., Kozin, S. V., Stylianopoulos, T., Mousa, A. S., Han, X., Adstamongkonkul, P., et al. (2013) · Nature Communications · doi:10.1038/ncomms3516 · Cited by 1,031 · cited 1×
“These data support the premise that collagen-mediated activation of DDR1 induces a signal pathway that includes PEAK1, SRC, and PYK2, which in turn are potentially responsible for collagen-induced chemoresistance (3, 39) and tumor progression.”
BackgroundThe Discoidin Domain Receptor Tyrosine Kinases Are Activated by Collagen
Vogel, W., Gish, G. D., Alves, F., & Pawson, T. (1997) · Molecular Cell · doi:10.1016/s1097-2765(00)80003-9 · Cited by 1,002 · cited 1×
“The DDR family includes DDR1 and DDR2, which are closely related collagen-specific receptor tyrosine kinases (RTK) that recognize and bind several types of collagen (5-7).”
BackgroundKadler, K. E., Baldock, C., Bella, J., & Boot-Handford, R. (2007) · Journal of Cell Science · doi:10.1242/jcs.03453 · Cited by 887 · cited 1×
“The DDR family includes DDR1 and DDR2, which are closely related collagen-specific receptor tyrosine kinases (RTK) that recognize and bind several types of collagen (5-7).”
BackgroundFuruyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.722 · Cited by 841 · cited 3×
“Sox9 is expressed in the malignant epithelium and is confined to the duct-like cells; differentiated acinar and endocrine cells do not express Sox9 (36, 37).”
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977
“These results depict a distinguish role of collagen in PDAC compared to other cancers.”
BackgroundInfluentialExtracellular matrix and its therapeutic potential for cancer treatment
Huang, J., Zhang, L., Wan, D., Zhou, L., Zheng, S., Lin, S., & Qiao, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00544-0 · Cited by 962
“Aguilera et al.(500) knocked down DDR1 by siRNA and found that migration was inhibited in pancreatic ductal adenocarcinoma cells.”
BackgroundPancreatic cancer stroma: an update on therapeutic targeting strategies
Hosein, A. N., Brekken, R. A., & Maitra, A. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0300-1 · Cited by 950
Self-citationThe role of collagen in cancer: from bench to bedside
Xu, S., Xu, H., Wang, W., Li, S., Li, H., Li, T., Zhang, W., Yu, X., & Liu, L. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-2058-1 · Cited by 735
Metadata
- Authors
- Aguilera, K. Y., Huang, H., Du, W., Hagopian, M. M., Wang, Z., Hinz, S., Hwang, T. H., Wang, H., Fleming, J. B., Castrillon, D. H., Ren, X., Ding, K., & Brekken, R. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Jinan University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- 6Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.
- Corresponding author
- Brekken, Rolf A.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2017-11-01
- Volume
- 16
- Issue
- 11
- Pages
- 2473-2485
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC5669827
- OpenAlex
- W2751614779
- Cited by
- 118
- References
- 61
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 17 · 2023: 12 · 2022: 15 · 2021: 16 · 2020: 15 · 2019: 15 · 2018: 9 · 2017: 1
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA118240, U54 CA210181, F31 CA168350)
- CPRIT (RP160211)
- National Science Fund (#81425021)
- Guangdong province (#2016A050502041)
- 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
- DDR1, pancreatic ductal adenocarcinoma, collagen signaling, extracellular matrix, Pyk2, PEAK1, kinase inhibitors, chemosensitization, tumor cell migration, tumor cell proliferation, combination chemotherapy
- MeSH terms
- Discoidin Domain Receptor 1, Adenocarcinoma, Animals, Cell Adhesion, Cell Movement, Collagen, Humans, Protein-Tyrosine Kinases, Signal Transduction, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Focal Adhesion Kinase 1, Small Molecule Libraries, Carcinogenesis
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