Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy
Open accessAbstract
The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:
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Treatment with a vitamin D receptor ligand caused activated stellate cells to revert to a more quiescent state and reduced disease aggressiveness.
“Treatment with a vitamin D receptor ligand caused activated stellate cells to revert to a more quiescent state and reduced disease aggressiveness23,147”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [23]
The Results section reports that the VDR ligand calcipotriol shifted pancreatic stellate cells toward a quiescent state. It also reports reduced tumor volume and improved survival in mice, but only when calcipotriol was combined with gemcitabine; calcipotriol alone had no measurable beneficial effect. The claim omits that condition for the reduction in disease aggressiveness. (LLM, conf=0.90)
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Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis
Bergers, G., Brekken, R., McMahon, G., Vu, T. H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z., et al. (2000) · Nature Cell Biology · doi:10.1038/35036374 · Cited by 2,797 · see citing works
Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., et al. (2012) · Nature · doi:10.1038/nature11183 · Cited by 1,771 · see citing works
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., et al. (2012) · Nature · doi:10.1038/nature11249 · Cited by 1,134 · see citing works
Bayne, L. J., Beatty, G. L., Jhala, N., Clark, C. E., Rhim, A. D., Stanger, B. Z., & Vonderheide, R. H. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.025 · Cited by 947 · see citing works
Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G., & Bar-Sagi, D. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.024 · Cited by 721 · see citing works
A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response
Ding, N., Yu, R. T., Subramaniam, N., Sherman, M. H., Wilson, C., Rao, R., Leblanc, M., Coulter, S., He, M., Scott, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.028 · Cited by 622 · see citing works
Self-citationIjichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Bierie, B., Tada, M., Mohri, D., Miyabayashi, K., Asaoka, Y., Maeda, S., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42754 · Cited by 256 · see citing works
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Research works printed but not linked: 53
- Aikawa T Gunn J Spong SM Klaus SJ Korc M 2006 Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer Molecular cancer therapeutics 5 1108 1116 16731742
- Apte MV Haber PS Applegate TL Norton ID McCaughan GW Korsten MA Pirola RC Wilson JS 1998 Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture Gut 43 128 133 9771417 PMC1727174
- Apte MV Pirola RC Wilson JS 2012 Pancreatic stellate cells: a starring role in normal and diseased pancreas Frontiers in physiology 3 344 22973234 PMC3428781
- Apte MV Wilson JS 2012 Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells Journal of gastroenterology and hepatology 27 Suppl 2 69 74 22320920
- Bailey JM Swanson BJ Hamada T Eggers JP Singh PK Caffery T Ouellette MM Hollingsworth MA 2008 Sonic hedgehog promotes desmoplasia in pancreatic cancer Clinical cancer research: an official journal of the American Association for Cancer Research 14 5995 6004 18829478 PMC2782957
- Bapiro TE Richards FM Goldgraben MA Olive KP Madhu B Frese KK Cook N Jacobetz MA Smith DM Tuveson DA 2011 A novel method for quantification of gemcitabine and its metabolites 2′,2′-difluorodeoxyuridine and gemcitabine triphosphate in tumour tissue by LC-MS/MS: comparison with (19)F NMR spectroscopy Cancer chemotherapy and pharmacology 68 1243 1253 21431415 PMC3215866
- Bardeesy N Aguirre AJ Chu GC Cheng KH Lopez LV Hezel AF Feng B Brennan C Weissleder R Mahmood U 2006 Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse Proceedings of the National Academy of Sciences of the United States of America 103 5947 5952 16585505 PMC1458678
- Bhowmick NA Neilson EG Moses HL 2004 Stromal fibroblasts in cancer initiation and progression Nature 432 332 337 15549095 PMC3050735
- Bissell MJ Hines WC 2011 Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression Nature medicine 17 320 329 PMC3569482 21383745
- Burris HA 3rd Moore MJ Andersen J Green MR Rothenberg ML Modiano MR Cripps MC Portenoy RK Storniolo AM Tarassoff P 1997 Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial Journal of clinical oncology: official journal of the American Society of Clinical Oncology 15 2403 2413 9196156
- Cantorna MT Hayes CE DeLuca HF 1996 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis Proceedings of the National Academy of Sciences of the United States of America 93 7861 7864 8755567 PMC38839
- Cantorna MT Hayes CE DeLuca HF 1998 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis The Journal of nutrition 128 68 72 9430604
- Cantorna MT Munsick C Bemiss C Mahon BD 2000 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease The Journal of nutrition 130 2648 2652 11053501
- Collisson EA Sadanandam A Olson P Gibb WJ Truitt M Gu S Cooc J Weinkle J Kim GE Jakkula L 2011 Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy Nature medicine 17 500 503 PMC3755490 21460848
- Collisson EA Trejo CL Silva JM Gu S Korkola JE Heiser LM Charles RP Rabinovich BA Hann B Dankort D 2012 A central role for RAF-->MEK-->ERK signaling in the genesis of pancreatic ductal adenocarcinoma Cancer discovery 2 685 693 22628411 PMC3425446
- Dowell NG Tofts PS 2007 Fast, accurate, and precise mapping of the RF field in vivo using the 180 degrees signal null Magnetic resonance in medicine: official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine 58 622 630 17763355
- Feig C Gopinathan A Neesse A Chan DS Cook N Tuveson DA 2012 The pancreas cancer microenvironment Clinical cancer research: an official journal of the American Association for Cancer Research 18 4266 4276 22896693 PMC3442232
- Fukuda A Wang SC Morris JPt Folias AE Liou A Kim GE Akira S Boucher KM Firpo MA Mulvihill SJ 2011 Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression Cancer cell 19 441 455 21481787 PMC3075548
- Garrido-Laguna I Uson M Rajeshkumar NV Tan AC de Oliveira E Karikari C Villaroel MC Salomon A Taylor G Sharma R 2011 Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer Clinical cancer research: an official journal of the American Association for Cancer Research 17 5793 5800 21742805 PMC3210576
- Heinemann V Haas M Boeck S 2012 Systemic treatment of advanced pancreatic cancer Cancer treatment reviews 38 843 853 22226241
- Hingorani SR Wang L Multani AS Combs C Deramaudt TB Hruban RH Rustgi AK Chang S Tuveson DA 2005 Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice Cancer cell 7 469 483 15894267
- Hwang RF Moore T Arumugam T Ramachandran V Amos KD Rivera A Ji B Evans DB Logsdon CD 2008 Cancer-associated stromal fibroblasts promote pancreatic tumor progression Cancer research 68 918 926 18245495 PMC2519173
- Jacobetz MA Chan DS Neesse A Bapiro TE Cook N Frese KK Feig C Nakagawa T Caldwell ME Zecchini HI 2012 Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer Gut PMC3551211 22466618
- Jacobetz MA Chan DS Neesse A Bapiro TE Cook N Frese KK Feig C Nakagawa T Caldwell ME Zecchini HI 2013 Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer Gut 62 112 120 22466618 PMC3551211
- Kalluri R Zeisberg M 2006 Fibroblasts in cancer Nature reviews Cancer 6 392 401 16572188
- Kisseleva T Cong M Paik Y Scholten D Jiang C Benner C Iwaisako K Moore-Morris T Scott B Tsukamoto H 2012 Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis Proceedings of the National Academy of Sciences of the United States of America 109 9448 9453 22566629 PMC3386114
- Lawler J 2002 Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth Journal of cellular and molecular medicine 6 1 12 12003665 PMC6740251
- Lesina M Kurkowski MU Ludes K Rose-John S Treiber M Kloppel G Yoshimura A Reindl W Sipos B Akira S 2011 Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer Cancer cell 19 456 469 21481788
- Ma Y Khalifa B Yee YK Lu J Memezawa A Savkur RS Yamamoto Y Chintalacharuvu SR Yamaoka K Stayrook KR 2006 Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators The Journal of clinical investigation 116 892 904 16528410 PMC1395481
- Mahadevan D Von Hoff DD 2007 Tumor-stroma interactions in pancreatic ductal adenocarcinoma Molecular cancer therapeutics 6 1186 1197 17406031
- Mantoni TS Lunardi S Al-Assar O Masamune A Brunner TB 2011 Pancreatic stellate cells radioprotect pancreatic cancer cells through beta1-integrin signaling Cancer research 71 3453 3458 21558392 PMC3097171
- Masamune A Shimosegawa T 2009 Signal transduction in pancreatic stellate cells Journal of gastroenterology 44 249 260 19271115
- Nagpal S Na S Rathnachalam R 2005 Noncalcemic actions of vitamin D receptor ligands Endocrine reviews 26 662 687 15798098
- Naveh-Many T Silver J 1993 Effects of calcitriol, 22-oxacalcitriol, and calcipotriol on serum calcium and parathyroid hormone gene expression Endocrinology 133 2724 2728 8243296
- Neesse A Frese KK Bapiro TE Nakagawa T Sternlicht MD Seeley TW Pilarsky C Jodrell DI Spong SM Tuveson DA 2013 CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer Proceedings of the National Academy of Sciences of the United States of America PMC3725120 23836645
- Olive KP Jacobetz MA Davidson CJ Gopinathan A McIntyre D Honess D Madhu B Goldgraben MA Caldwell ME Allard D 2009 Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer Science 324 1457 1461 19460966 PMC2998180
- Omary MB Lugea A Lowe AW Pandol SJ 2007 The pancreatic stellate cell: a star on the rise in pancreatic diseases The Journal of clinical investigation 117 50 59 17200706 PMC1716214
- Persons KS Eddy VJ Chadid S Deoliveira R Saha AK Ray R 2010 Anti-growth effect of 1,25-dihydroxyvitamin D3-3-bromoacetate alone or in combination with 5-amino-imidazole-4-carboxamide-1-beta-4-ribofuranoside in pancreatic cancer cells Anticancer research 30 1875 1880 20651329
- Phillips PA McCarroll JA Park S Wu MJ Pirola R Korsten M Wilson JS Apte MV 2003 Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover Gut 52 275 282 12524413 PMC1774949
- Pietras K Ostman A 2010 Hallmarks of cancer: interactions with the tumor stroma Experimental cell research 316 1324 1331 20211171
- Provenzano PP Cuevas C Chang AE Goel VK Von Hoff DD Hingorani SR 2012 Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma Cancer cell 21 418 429 22439937 PMC3371414
- Rasanen K Vaheri A 2010 Activation of fibroblasts in cancer stroma Experimental cell research 316 2713 2722 20451516
- Schneider E Schmid-Kotsas A Zhao J Weidenbach H Schmid RM Menke A Adler G Waltenberger J Grunert A Bachem MG 2001 Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells American journal of physiology Cell physiology 281 C532 543 11443052
- Shimoda M Mellody KT Orimo A 2010 Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression Seminars in cell & developmental biology 21 19 25 19857592 PMC2828545
- Skinner HG Michaud DS Giovannucci E Willett WC Colditz GA Fuchs CS 2006 Vitamin D intake and the risk for pancreatic cancer in two cohort studies Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 15 1688 1695 16985031
- Vonlaufen A Joshi S Qu C Phillips PA Xu Z Parker NR Toi CS Pirola RC Wilson JS Goldstein D 2008 Pancreatic stellate cells: partners in crime with pancreatic cancer cells Cancer research 68 2085 2093 18381413
- Wehr AY Furth EE Sangar V Blair IA Yu KH 2011 Analysis of the human pancreatic stellate cell secreted proteome Pancreas 40 557 566 21499210 PMC3086313
- Willemer S Elsasser HP Adler G 1992 Hormone-induced pancreatitis European surgical research Europaische chirurgische Forschung Recherches chirurgicales europeennes 24 Suppl 1 29 39 1601022
- Wolpin BM Ng K Bao Y Kraft P Stampfer MJ Michaud DS Ma J Buring JE Sesso HD Lee IM 2012 Plasma 25-hydroxyvitamin D and risk of pancreatic cancer Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 21 82 91 PMC3253914 22086883
- Yanagisawa J Yanagi Y Masuhiro Y Suzawa M Watanabe M Kashiwagi K Toriyabe T Kawabata M Miyazono K Kato S 1999 Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators Science 283 1317 1321 10037600
- Yoshizawa T Handa Y Uematsu Y Takeda S Sekine K Yoshihara Y Kawakami T Arioka K Sato H Uchiyama Y 1997 Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning Nature genetics 16 391 396 9241280
- Yu WD Ma Y Flynn G Muindi JR Kong RX Trump DL Johnson CS 2010 Calcitriol enhances gemcitabine anti-tumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system Cell Cycle 9 3022 3029 20699664 PMC3040927
- Zeitz U Weber K Soegiarto DW Wolf E Balling R Erben RG 2003 Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor FASEB journal: official publication of the Federation of American Societies for Experimental Biology 17 509 511 12551842
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Winograd, R., Byrne, K. T., Evans, R. A., Odorizzi, P. M., Meyer, A. R. L., Bajor, D. L., Clendenin, C., Stanger, B. Z., Furth, E. E., Wherry, E. J., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0215 · Cited by 459 · see citing works
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Self-citationZhang, Y., Lazarus, J., Steele, N. G., Yan, W., Lee, H.-J., Nwosu, Z. C., Halbrook, C. J., Menjivar, R. E., Kemp, S. B., Sirihorachai, V. R., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0958 · Cited by 385 · see citing works
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Han, L., Wu, Y., Fang, K., Sweeney, S., Roesner, U. K., Parrish, M., Patel, K., Walter, T., Piermattei, J., Trimboli, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-34464-6 · Cited by 369 · see citing works
Han, X., Li, Y., Xu, Y., Zhao, X., Zhang, Y., Yang, X., Wang, Y., Zhao, R., Anderson, G. J., Zhao, Y., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05906-x · Cited by 339 · see citing works
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Vennin, C., Mélénec, P., Rouet, R., Nobis, M., Cazet, A. S., Murphy, K. J., Herrmann, D., Reed, D. A., Lucas, M. C., Warren, S. C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10968-6 · Cited by 268 · see citing works
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Chen, M., Mao, A., Xu, M., Weng, Q., Mao, J., & Ji, J. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.01.017 · Cited by 272 · see citing works
Rahbari, N. N., Kedrin, D., Incio, J., Liu, H., Ho, W. W., Nia, H. T., Edrich, C. M., Jung, K., Daubriac, J., Chen, I., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf5219 · Cited by 258 · see citing works
Mhaidly, R., & Mechta‐Grigoriou, F. (2021) · Immunological Reviews · doi:10.1111/imr.12978 · Cited by 231 · see citing works
Helms, E. J., Berry, M. W., Chaw, R. C., DuFort, C. C., Sun, D., Onate, M. K., Oon, C., Bhattacharyya, S., Sanford-Crane, H., Horton, W., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0601 · Cited by 238 · see citing works
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Miao, L., Liu, Q., Lin, C. M., Luo, C., Wang, Y., Liu, L., Yin, W., Hu, S., Kim, W. Y., & Huang, L. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-0866 · Cited by 215 · see citing works
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Avery, D., Govindaraju, P., Jacob, M., Todd, L., Monslow, J., & Puré, E. (2018) · Matrix Biology · doi:10.1016/j.matbio.2017.12.003 · Cited by 206 · see citing works
Zhu, Z., Achreja, A., Meurs, N., Animasahun, O., Owen, S., Mittal, A., Parikh, P., Lo, T.-W., Franco-Barraza, J., Shi, J., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0226-5 · Cited by 204 · see citing works
Self-citationBelow, C. R., Kelly, J., Brown, A., Humphries, J. D., Hutton, C., Xu, J., Lee, B. Y., Cintas, C., Zhang, X., Hernandez-Gordillo, V., et al. (2022) · Nature Materials · doi:10.1038/s41563-021-01085-1 · Cited by 194 · see citing works
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Fabris, L., Perugorria, M. J., Mertens, J., Björkström, N. K., Cramer, T., Lleo, A., Solinas, A., Sänger, H., Lukacs‐Kornek, V., Moncsek, A., et al. (2019) · Liver International · doi:10.1111/liv.14098 · Cited by 187 · see citing works
Nanoformulations for combination or cascade anticancer therapy
Miao, L., Guo, S., Lin, C. M., Liu, Q., & Huang, L. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.06.003 · Cited by 178 · see citing works
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma
Krah, N. M., De La O, J.-P., Swift, G. H., Hoang, C. Q., Willet, S. G., Chen Pan, F., Cash, G. M., Bronner, M. P., Wright, C. V., MacDonald, R. J., et al. (2015) · eLife · doi:10.7554/elife.07125 · Cited by 166 · see citing works
Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
Madsen, C. D., Pedersen, J. T., Venning, F. A., Singh, L. B., Moeendarbary, E., Charras, G., Cox, T. R., Sahai, E., & Erler, J. T. (2015) · The EMBO Reports · doi:10.15252/embr.201540107 · Cited by 157 · see citing works
Stromal cues regulate the pancreatic cancer epigenome and metabolome
Sherman, M. H., Yu, R. T., Tseng, T. W., Sousa, C. M., Liu, S., Truitt, M. L., He, N., Ding, N., Liddle, C., Atkins, A. R., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620164114 · Cited by 147 · see citing works
Self-citationModulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery
Zhang, B., Hu, Y., & Pang, Z. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00952 · Cited by 152 · see citing works
Vitamin D regulates microbiome-dependent cancer immunity
Giampazolias, E., Pereira da Costa, M., Lam, K. C., Lim, K. H. J., Cardoso, A., Piot, C., Chakravarty, P., Blasche, S., Patel, S., Biram, A., et al. (2024) · Science · doi:10.1126/science.adh7954 · Cited by 151 · see citing works
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
Porter, R. L., Magnus, N. K. C., Thapar, V., Morris, R., Szabolcs, A., Neyaz, A., Kulkarni, A. S., Tai, E., Chougule, A., Hillis, A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1914915116 · Cited by 129 · see citing works
Self-citationChemotherapy and tumor microenvironment of pancreatic cancer
Liu, Q., Liao, Q., & Zhao, Y. (2017) · Cancer Cell International · doi:10.1186/s12935-017-0437-3 · Cited by 120 · see citing works
Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma
Garcia, P. E., Adoumie, M., Kim, E. C., Zhang, Y., Scales, M. K., El-Tawil, Y. S., Shaikh, A. Z., Wen, H.-J., Bednar, F., Allen, B. L., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.05.004 · Cited by 110 · see citing works
Epithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108 · see citing works
Franco-Barraza, J., Francescone, R., Luong, T., Shah, N., Madhani, R., Cukierman, G., Dulaimi, E., Devarajan, K., Egleston, B. L., Nicolas, E., et al. (2017) · eLife · doi:10.7554/elife.20600 · Cited by 112 · see citing works
Determinants and functions of CAFs secretome during cancer progression and therapy
Linares, J., Marín-Jiménez, J. A., Badia-Ramentol, J., & Calon, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.621070 · Cited by 110 · see citing works
Cancer‐Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin
Wang, Z., Yang, Q., Tan, Y., Tang, Y., Ye, J., Yuan, B., & Yu, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.613534 · Cited by 81 · see citing works
Fibroblasts as Modulators of Local and Systemic Cancer Metabolism
Sanford-Crane, H., Abrego, J., & Sherman, M. H. (2019) · Cancers · doi:10.3390/cancers11050619 · Cited by 77 · see citing works
Self-citationMalik, R., Luong, T., Cao, X., Han, B., Shah, N., Franco-Barraza, J., Han, L., Shenoy, V. B., Lelkes, P. I., & Cukierman, E. (2019) · Matrix Biology · doi:10.1016/j.matbio.2018.11.001 · Cited by 74 · see citing works
Management of chronic pancreatitis
Hines, O. J., & Pandol, S. J. (2024) · BMJ · doi:10.1136/bmj-2023-070920 · Cited by 58 · see citing works
Han, B., Qu, C., Park, K., Konieczny, S. F., & Korc, M. (2016) · Cancer Letters · doi:10.1016/j.canlet.2015.12.003 · Cited by 53 · see citing works
Ruggeri, J. M., Franco-Barraza, J., Sohail, A., Zhang, Y., Long, D., Pasca di Magliano, M., Cukierman, E., Fridman, R., & Crawford, H. C. (2020) · The American Journal of Pathology · doi:10.1016/j.ajpath.2020.03.020 · Cited by 40 · see citing works
Targeting autophagy as a therapeutic strategy against pancreatic cancer
Yamamoto, K., Iwadate, D., Kato, H., Nakai, Y., Tateishi, K., & Fujishiro, M. (2022) · Journal of Gastroenterology · doi:10.1007/s00535-022-01889-1 · Cited by 29 · see citing works
Current Status of Research on Losartan in Tumour Therapy
Wang, H., Yuan, S., & Wang, H. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70985 · Cited by 11 · see citing works
Hu, C., Yin, L., Chen, Z., Waldron, R. T., Lugea, A., Lin, Y., Zhai, X., Wen, L., Han, Y.-P., Pandol, S. J., et al. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.11.031 · Cited by 8 · see citing works
- Authors
- Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., Martin, P., Tseng, T. W., Dawson, D. W., Donahue, T. R., Masamune, A., Shimosegawa, T., Apte, M. V., Wilson, J. S., Ng, B., Lau, S. L., Gunton, J. E., Wahl, G. M., Hunter, T., Drebin, J. A., O’Dwyer, P. J., Liddle, C., Tuveson, D. A., Downes, M., & Evans, R. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Cold Spring Harbor Laboratory (US)
- University of California, San Francisco (US)
- Cancer Research UK (GB)
- Frederick National Laboratory for Cancer Research (US)
- University of California, Los Angeles (US)
- Tohoku University (JP)
- UNSW Sydney (AU)
- Garvan Institute of Medical Research (AU)
- The University of Sydney (AU)
- Hospital of the University of Pennsylvania (US)
- Corresponding author
- Downes, Michael
- Evans, Ronald M.
- ORCID
- Sherman, Mara H.
- Yu, Ruth T.
- Engle, Dannielle D.
- Ding, Ning
- Atkins, Annette R.
- Collisson, Eric A.
- Connor, Frances
- Tseng, Tiffany W.
- Dawson, David W.
- Donahue, Timothy R.
- Masamune, Atsushi
- Shimosegawa, Tooru
- Apte, Minoti V.
- Wilson, Jeremy S.
- Ng, Beverly
- Lau, Sue Lynn
- Gunton, Jenny E.
- Wahl, Geoffrey M.
- Hunter, Tony
- Drebin, Jeffrey A.
- Liddle, Christopher
- Tuveson, David A.
- Downes, Michael
- Evans, Ronald M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 159
- Issue
- 1
- Pages
- 80-93
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4177038
- OpenAlex
- W2137217704
- Cited by
- 1,158
- References
- 7
- Citations by year
- 2026: 75 · 2025: 81 · 2024: 98 · 2023: 113 · 2022: 123 · 2021: 118 · 2020: 133 · 2019: 86 · 2018: 98 · 2017: 84 · 2016: 78 · 2015: 65 · 2014: 6
- FWCI
- 37.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p30ca045508-35)
- National Heart, Lung, and Blood Institute (HL105278, R01HL105278)
- National Cancer Institute (CA014195, T32CA148056, P01CA163200, P30-CA045508, T32CA009370, P30CA014195)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK0577978, R24DK090962, DK090962)
- National Institute of Environmental Health Sciences (P42ES010337, ES 010337)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Keywords
- vitamin D receptor, calcipotriol, pancreatic ductal adenocarcinoma, pancreatic stellate cells, pancreatitis, gemcitabine, chemoresistance, stromal fibrosis, inflammation, transcriptional regulation, stromal remodeling
- MeSH terms
- Adenocarcinoma, Animals, Antineoplastic Agents, Calcitriol, Disease Models, Animal, Humans, Mice, Inbred C57BL, Molecular Sequence Data, Pancreatic Neoplasms, Pancreatitis, Signal Transduction, Stromal Cells, Receptors, Calcitriol, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, Cell Line, Tumor
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