Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma

Andrew D. Rhim; Paul E. Oberstein; Dafydd H. Thomas; Emily T. Mirek; Carmine F. Palermo; Stephen A. Sastra; Erin N. Dekleva; Tyler Saunders; Claudia P. Becerra; Ian W. Tattersall; C. Benedikt Westphalen; Jan Kitajewski; Maite G. Fernandez-Barrena; Martin E. Fernandez-Zapico; Christine Iacobuzio-Donahue; Kenneth P. Olive; Ben Z. Stanger

doi:10.1016/j.ccr.2014.04.021

Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma

Andrew D. Rhim, Paul E. Oberstein, Dafydd H. Thomas, Emily T. Mirek, Carmine F. Palermo, Stephen A. Sastra, Erin N. Dekleva, Tyler Saunders, Claudia P. Becerra, Ian W. Tattersall, C. Benedikt Westphalen, Jan Kitajewski, Maite G. Fernandez-Barrena, Martin E. Fernandez-Zapico, Christine Iacobuzio-Donahue, Kenneth P. Olive, Ben Z. Stanger

School of Medicine

Research output: Contribution to journal › Article

Abstract

Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.

Original language	English (US)
Pages (from-to)	735-747
Number of pages	13
Journal	Cancer cell
Volume	25
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2014.04.021
State	Published - Jun 16 2014

Fingerprint

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Cite this

Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., Dekleva, E. N., Saunders, T., Becerra, C. P., Tattersall, I. W., Westphalen, C. B., Kitajewski, J., Fernandez-Barrena, M. G., Fernandez-Zapico, M. E., Iacobuzio-Donahue, C., Olive, K. P., & Stanger, B. Z. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer cell, 25(6), 735-747. https://doi.org/10.1016/j.ccr.2014.04.021

Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. / Rhim, Andrew D.; Oberstein, Paul E.; Thomas, Dafydd H.; Mirek, Emily T.; Palermo, Carmine F.; Sastra, Stephen A.; Dekleva, Erin N.; Saunders, Tyler; Becerra, Claudia P.; Tattersall, Ian W.; Westphalen, C. Benedikt; Kitajewski, Jan; Fernandez-Barrena, Maite G.; Fernandez-Zapico, Martin E.; Iacobuzio-Donahue, Christine; Olive, Kenneth P.; Stanger, Ben Z.

In: Cancer cell, Vol. 25, No. 6, 16.06.2014, p. 735-747.

Research output: Contribution to journal › Article

Rhim, AD, Oberstein, PE, Thomas, DH, Mirek, ET, Palermo, CF, Sastra, SA, Dekleva, EN, Saunders, T, Becerra, CP, Tattersall, IW, Westphalen, CB, Kitajewski, J, Fernandez-Barrena, MG, Fernandez-Zapico, ME, Iacobuzio-Donahue, C, Olive, KP & Stanger, BZ 2014, 'Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma', Cancer cell, vol. 25, no. 6, pp. 735-747. https://doi.org/10.1016/j.ccr.2014.04.021

Rhim, Andrew D. ; Oberstein, Paul E. ; Thomas, Dafydd H. ; Mirek, Emily T. ; Palermo, Carmine F. ; Sastra, Stephen A. ; Dekleva, Erin N. ; Saunders, Tyler ; Becerra, Claudia P. ; Tattersall, Ian W. ; Westphalen, C. Benedikt ; Kitajewski, Jan ; Fernandez-Barrena, Maite G. ; Fernandez-Zapico, Martin E. ; Iacobuzio-Donahue, Christine ; Olive, Kenneth P. ; Stanger, Ben Z. / Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. In: Cancer cell. 2014 ; Vol. 25, No. 6. pp. 735-747.

@article{22ad3c9eb3484cad8f7bc6d047c0f3fd,

title = "Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma",

abstract = "Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.",

author = "Rhim, {Andrew D.} and Oberstein, {Paul E.} and Thomas, {Dafydd H.} and Mirek, {Emily T.} and Palermo, {Carmine F.} and Sastra, {Stephen A.} and Dekleva, {Erin N.} and Tyler Saunders and Becerra, {Claudia P.} and Tattersall, {Ian W.} and Westphalen, {C. Benedikt} and Jan Kitajewski and Fernandez-Barrena, {Maite G.} and Fernandez-Zapico, {Martin E.} and Christine Iacobuzio-Donahue and Olive, {Kenneth P.} and Stanger, {Ben Z.}",

year = "2014",

month = jun,

day = "16",

doi = "10.1016/j.ccr.2014.04.021",

language = "English (US)",

volume = "25",

pages = "735--747",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma

AU - Rhim, Andrew D.

AU - Oberstein, Paul E.

AU - Thomas, Dafydd H.

AU - Mirek, Emily T.

AU - Palermo, Carmine F.

AU - Sastra, Stephen A.

AU - Dekleva, Erin N.

AU - Saunders, Tyler

AU - Becerra, Claudia P.

AU - Tattersall, Ian W.

AU - Westphalen, C. Benedikt

AU - Kitajewski, Jan

AU - Fernandez-Barrena, Maite G.

AU - Fernandez-Zapico, Martin E.

AU - Iacobuzio-Donahue, Christine

AU - Olive, Kenneth P.

AU - Stanger, Ben Z.

PY - 2014/6/16

Y1 - 2014/6/16

N2 - Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.

AB - Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.

UR - http://www.scopus.com/inward/record.url?scp=84902435628&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902435628&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2014.04.021

DO - 10.1016/j.ccr.2014.04.021

M3 - Article

C2 - 24856585

AN - SCOPUS:84902435628

VL - 25

SP - 735

EP - 747

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 6

ER -

Access to Document

10.1016/j.ccr.2014.04.021