TY - JOUR
T1 - Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival
AU - Özdemir, Berna C.
AU - Pentcheva-Hoang, Tsvetelina
AU - Carstens, Julienne L.
AU - Zheng, Xiaofeng
AU - Wu, Chia Chin
AU - Simpson, Tyler R.
AU - Laklai, Hanane
AU - Sugimoto, Hikaru
AU - Kahlert, Christoph
AU - Novitskiy, Sergey V.
AU - DeJesus-Acosta, Ana
AU - Sharma, Padmanee
AU - Heidari, Pedram
AU - Mahmood, Umar
AU - Chin, Lynda
AU - Moses, Harold L.
AU - Weaver, Valerie M.
AU - Maitra, Anirban
AU - Allison, James P.
AU - LeBleu, Valerie S.
AU - Kalluri, Raghu
N1 - Funding Information:
We wish to thank Travis Hardcastle, Lauren Bizarro, Judith Kaye, Laura Gibson, and Sara Lovisa for genotyping and animal husbandry support; Donna Reynolds for IHC stainings; and Travis Hardcastle, Dr. Ganiraju C. Manyam, Dr. Jing Wang, and the Bioinformatics and Computational Biology Department at MDACC for bioinformatic support. This study was supported primarily by NIH grant UO1 CA151925. B.C.O. received funding from the OncoSuisse MD/PhD Scholarship (323630-128865/1) and the Swiss National Science Foundation Fellowship (PBBEP3_144809). C.K. is funded by a Research Fellowship of Deutsche Forschungsgemeinschaft. A.M. is supported by NIH grant CA113669. R.K. is supported by the Cancer Prevention and Research Institute of Texas and the Metastasis Research Center at MD Anderson Cancer Center, NIH grants DK55001, DK81976, CA125550, CA155370, and CA163191. J.P.A. is an inventor of intellectual property owned by the University of California, Berkeley, and licensed to Bristol Myers-Squibb.
PY - 2014/6/16
Y1 - 2014/6/16
N2 - Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
AB - Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
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U2 - 10.1016/j.ccr.2014.04.005
DO - 10.1016/j.ccr.2014.04.005
M3 - Article
C2 - 24856586
AN - SCOPUS:84902469661
SN - 1535-6108
VL - 25
SP - 719
EP - 734
JO - Cancer cell
JF - Cancer cell
IS - 6
ER -