Stromal response to Hedgehog signaling restrains pancreatic cancer progression
Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA p...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 30; pp. E3091 - E3100 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
29.07.2014
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention. |
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| AbstractList | Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention. Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention. 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. Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention. |
| Author | Philip A. Beachy Vikram Deshpande Yves Boucher Sally Kawano John J. Lee Huaijun Wang James K. Chen Rushika M. Perera Krishna S. Ghanta Shiwei Han Nabeel Bardeesy Tomoyo Kato Jürgen K. Willmann Julien Fitamant Julia M. Nagle Dai-Chen Wu Phillip D. Jones X. Shawn Liu |
| Author_xml | – sequence: 1 givenname: John J. surname: Lee fullname: Lee, John J. organization: Institute for Stem Cell Biology and Regenerative Medicine,, Division of Oncology, Department of Medicine – sequence: 2 givenname: Rushika M. surname: Perera fullname: Perera, Rushika M. organization: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 – sequence: 3 givenname: Huaijun surname: Wang fullname: Wang, Huaijun organization: Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 – sequence: 4 givenname: Dai-Chen surname: Wu fullname: Wu, Dai-Chen organization: Institute for Stem Cell Biology and Regenerative Medicine – sequence: 5 givenname: X. Shawn surname: Liu fullname: Liu, X. Shawn organization: Institute for Stem Cell Biology and Regenerative Medicine – sequence: 6 givenname: Shiwei surname: Han fullname: Han, Shiwei organization: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and – sequence: 7 givenname: Julien surname: Fitamant fullname: Fitamant, Julien organization: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 – sequence: 8 givenname: Phillip D. surname: Jones fullname: Jones, Phillip D. organization: Institute for Stem Cell Biology and Regenerative Medicine – sequence: 9 givenname: Krishna S. surname: Ghanta fullname: Ghanta, Krishna S. organization: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 – sequence: 10 givenname: Sally surname: Kawano fullname: Kawano, Sally organization: Institute for Stem Cell Biology and Regenerative Medicine – sequence: 11 givenname: Julia M. surname: Nagle fullname: Nagle, Julia M. organization: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 – sequence: 12 givenname: Vikram surname: Deshpande fullname: Deshpande, Vikram organization: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 – sequence: 13 givenname: Yves surname: Boucher fullname: Boucher, Yves organization: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and – sequence: 14 givenname: Tomoyo surname: Kato fullname: Kato, Tomoyo organization: Department of Chemical and Systems Biology, and – sequence: 15 givenname: James K. surname: Chen fullname: Chen, James K. organization: Department of Chemical and Systems Biology, and – sequence: 16 givenname: Jürgen K. surname: Willmann fullname: Willmann, Jürgen K. organization: Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 – sequence: 17 givenname: Nabeel surname: Bardeesy fullname: Bardeesy, Nabeel organization: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 – sequence: 18 givenname: Philip A. surname: Beachy fullname: Beachy, Philip A. organization: Institute for Stem Cell Biology and Regenerative Medicine,, Department of Biochemistry,, Howard Hughes Medical Institute, Stanford, CA 94305 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25024225$$D View this record in MEDLINE/PubMed |
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| Notes | http://dx.doi.org/10.1073/pnas.1411679111 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Author contributions: J.J.L., R.M.P., Y.B., J.K.W., N.B., and P.A.B. designed research; J.J.L., R.M.P., H.W., D.-C.W., X.S.L., S.H., J.F., P.D.J., K.S.G., S.K., J.M.N., and V.D. performed research; T.K. and J.K.C. contributed new reagents/analytic tools; J.J.L., R.M.P., H.W., S.H., J.F., V.D., N.B., and P.A.B. analyzed data; and J.J.L., R.M.P., N.B., and P.A.B. wrote the paper. 1J.J.L. and R.M.P. contributed equally to this work. 2H.W., D.-C.W., and X.S.L. contributed equally to this work. Reviewers: B.L., University of Massachusetts Medical School; and A.M., University of Texas MD Anderson Cancer Center. Contributed by Philip A. Beachy, June 23, 2014 (sent for review May 27, 2014; reviewed by Brian Lewis and Anirban Maitra) |
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| Snippet | Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical... Preclinical studies have suggested that Hedgehog (Hh) pathway inhibition reduces growth and metastasis of pancreatic ductal adenocarcinoma (PDA), but ensuing... |
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| SubjectTerms | adenocarcinoma agonists animal models Animals Biological Sciences carcinogenesis Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology clinical trials epithelium fibroblasts Genetic engineering Hedgehog Proteins - antagonists & inhibitors Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Humans hyperplasia ligands Mice Mice, Knockout Molecules Pancreatic cancer pancreatic neoplasms Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Pharmacology PNAS Plus Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism Rodents Signal Transduction |
| Title | Stromal response to Hedgehog signaling restrains pancreatic cancer progression |
| URI | http://www.pnas.org/content/111/30/E3091.abstract https://www.ncbi.nlm.nih.gov/pubmed/25024225 https://www.proquest.com/docview/1551735479 https://www.proquest.com/docview/1550076769 https://www.proquest.com/docview/1803094768 https://pubmed.ncbi.nlm.nih.gov/PMC4121834 |
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