Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Mara H. Sherman; Ruth T. Yu; Dannielle D. Engle; Ning Ding; Annette R. Atkins; Herve Tiriac; Eric A. Collisson; Frances Connor; Terry Van Dyke; Serguei Kozlov; Philip Martin; Tiffany W. Tseng; David W. Dawson; Timothy R. Donahue; Atsushi Masamune; Tooru Shimosegawa; Minoti V. Apte; Jeremy S. Wilson; Beverly Ng; Sue Lynn Lau; Jenny E. Gunton; Geoffrey M. Wahl; Tony Hunter; Jeffrey A. Drebin; Peter J. O'Dwyer; Christopher Liddle; David A. Tuveson; Michael Downes; Ronald M. Evans

doi:10.1016/j.cell.2014.08.007

Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Mara H. Sherman, Ruth T. Yu, Dannielle D. Engle, Ning Ding, Annette R. Atkins, Herve Tiriac, Eric A. Collisson, Frances Connor, Terry Van Dyke, Serguei Kozlov, Philip Martin, Tiffany W. Tseng, David W. Dawson, Timothy R. Donahue, Atsushi Masamune, Tooru Shimosegawa, Minoti V. Apte, Jeremy S. Wilson, Beverly Ng, Sue Lynn LauJenny E. Gunton, Geoffrey M. Wahl, Tony Hunter, Jeffrey A. Drebin, Peter J. O'Dwyer, Christopher Liddle, David A. Tuveson, Michael Downes, Ronald M. Evans

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English (US)
Pages (from-to)	80-93
Number of pages	14
Journal	Cell
Volume	159
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2014.08.007
State	Published - Sep 25 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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., ... Evans, R. M. (2014). Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell, 159(1), 80-93. https://doi.org/10.1016/j.cell.2014.08.007

Sherman, MH, Yu, RT, Engle, DD, Ding, N, Atkins, AR, Tiriac, H, Collisson, EA, Connor, F, Van Dyke, T, Kozlov, S, Martin, P, Tseng, TW, Dawson, DW, Donahue, TR, Masamune, A, Shimosegawa, T, Apte, MV, Wilson, JS, Ng, B, Lau, SL, Gunton, JE, Wahl, GM, Hunter, T, Drebin, JA, O'Dwyer, PJ, Liddle, C, Tuveson, DA, Downes, M & Evans, RM 2014, 'Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy', Cell, vol. 159, no. 1, pp. 80-93. https://doi.org/10.1016/j.cell.2014.08.007

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abstract = "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.",

author = "Sherman, {Mara H.} and Yu, {Ruth T.} and Engle, {Dannielle D.} and Ning Ding and Atkins, {Annette R.} and Herve Tiriac and Collisson, {Eric A.} and Frances Connor and {Van Dyke}, Terry and Serguei Kozlov and Philip Martin and Tseng, {Tiffany W.} and Dawson, {David W.} and Donahue, {Timothy R.} and Atsushi Masamune and Tooru Shimosegawa and Apte, {Minoti V.} and Wilson, {Jeremy S.} and Beverly Ng and Lau, {Sue Lynn} and Gunton, {Jenny E.} and Wahl, {Geoffrey M.} and Tony Hunter and Drebin, {Jeffrey A.} and O'Dwyer, {Peter J.} and Christopher Liddle and Tuveson, {David A.} and Michael Downes and Evans, {Ronald M.}",

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AU - Atkins, Annette R.

AU - Tiriac, Herve

AU - Collisson, Eric A.

AU - Connor, Frances

AU - Van Dyke, Terry

AU - Kozlov, Serguei

AU - Martin, Philip

AU - Tseng, Tiffany W.

AU - Dawson, David W.

AU - Donahue, Timothy R.

AU - Masamune, Atsushi

AU - Shimosegawa, Tooru

AU - Apte, Minoti V.

AU - Wilson, Jeremy S.

AU - Ng, Beverly

AU - Lau, Sue Lynn

AU - Gunton, Jenny E.

AU - Wahl, Geoffrey M.

AU - Hunter, Tony

AU - Drebin, Jeffrey A.

AU - O'Dwyer, Peter J.

AU - Liddle, Christopher

AU - Tuveson, David A.

AU - Downes, Michael

AU - Evans, Ronald M.

PY - 2014/9/25

Y1 - 2014/9/25

N2 - 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.

AB - 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.

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Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Abstract

ASJC Scopus subject areas

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