Stromal response to Hedgehog signaling restrains pancreatic cancer progression
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Significance: Preclinical studies have suggested that Hedgehog (Hh) pathway inhibition reduces growth and metastasis of pancreatic ductal adenocarcinoma (PDA), but ensuing clinical trials of Hh pathway antagonists combined with cytotoxic chemotherapy have not succeeded. Here, we find in three distinct genetically engineered mouse models that genetic and pharmacologic inhibition of Hh pathway activity actually accelerates PDA progression. Furthermore, we find that the acute modulation of pathway activity regulates the balance between epithelial and stromal elements, with inhibition causing suppression of desmoplasia and accelerated growth of epithelial elements and activation causing stromal hyperplasia and reduced growth of the neoplastic epithelium. Our study explains previous clinical trial results and suggests the possibility of novel types of therapeutic interventions.
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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 [160]
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Perez, V. M., Kearney, J. F., & Yeh, J. J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.751311 · Cited by 143 · see citing works
Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix
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Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes
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Fibroblasts as Modulators of Local and Systemic Cancer Metabolism
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- Authors
- Lee, J. J., Perera, R. M., Wang, H., Wu, D.-C., Liu, X. S., Han, S., Fitamant, J., Jones, P. D., Ghanta, K. S., Kawano, S., Nagle, J. M., Deshpande, V., Boucher, Y., Kato, T., Chen, J. K., Willmann, J. K., Bardeesy, N., & Beachy, P. A.
- Affiliations
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Harvard University (US)
- Stanford Medicine (US)
- Department of Chemical and Systems Biology, and
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-07-14
- Volume
- 111
- Issue
- 30
- Pages
- E3091-100
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4121834
- OpenAlex
- W1971298987
- Cited by
- 502
- References
- 52
- Citations by year
- 2026: 26 · 2025: 23 · 2024: 31 · 2023: 43 · 2022: 44 · 2021: 61 · 2020: 49 · 2019: 46 · 2018: 41 · 2017: 43 · 2016: 50 · 2015: 37 · 2014: 8
- FWCI
- 18.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA136574, P50CA1270003, R01CA133557, R21CA158640, R01CA155289, P01CA117969)
- National Institute of General Medical Sciences (P50GM107615)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- Hedgehog signaling, pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia, tumor stroma, desmoplasia, stromal hyperplasia, Hedgehog pathway inhibition, tumor microenvironment, genetically engineered mouse models, pancreatic cancer progression
- MeSH terms
- Animals, Humans, Pancreatic Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Carcinoma, Pancreatic Ductal, Mice, Hedgehog Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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