TY - JOUR
T1 - INOS regulates the therapeutic response of pancreatic cancer cells to radiotherapy A C
AU - Pereira, Patricia M.R.
AU - Edwards, Kimberly J.
AU - Mandleywala, Komal
AU - Carter, Lukas M.
AU - Escorcia, Freddy E.
AU - Campesato, Luis Felipe
AU - Cornejo, Mike
AU - Abma, Lolkje
AU - Mohsen, Abu Akeel
AU - Iacobuzio-Donahue, Christine A.
AU - Merghoub, Taha
AU - Lewis, Jason S.
N1 - Funding Information:
The authors acknowledge the Radiochemistry and Molecular Imaging Probe Core, the Antitumor Assessment Core, and Molecular Cytology Core Facility, which were supported by NIH grant P30 CA08748. This study was supported in part by the Geoffrey Beene Cancer Research Center of MSKCC (to J.S. Lewis) and NIH NCI R35 CA232130 (to J.S. Lewis). We gratefully acknowledge Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics of MSKCC. P.M.R. Pereira acknowledges the Tow Foundation Postdoctoral Fellowship from the MSKCC Center for Molecular Imaging and Nanotechnology and the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of MSKCC. L.M. Carter acknowledges support from the Ruth L. Kirschstein National Research Service Award postdoctoral fellowship (NIH F32-EB025050). T. Merghoub and L.F. Campesato are supported by Swim Across America, Ludwig Institute for Cancer Research, Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering, Cancer Research Institute, Parker Institute for Cancer Immunotherapy and Breast Cancer Research Foundation. Figures 2A, 4H, and 4J were created with Biorender. We thank Dr. Russel and Dr. Monette for their help with the Arc Therapy and image analysis, respectively. We thank Egger for cutting the human samples used in this work. We thank Carl DeSelm in the Michel Sadelain lab for generating the FC1245luc+ PDAC cells.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/4/15
Y1 - 2020/4/15
N2 - Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and the response of PDAC cells to radiotherapy are unknown. Using patient samples and orthotopic PDAC biological models, we showed that radiotherapy increased inducible nitric oxide synthase (iNOS) in the tumor tissues. Mechanistic in vitro studies showed that, although undetectable in radiotherapy-activated tumor cells, iNOS expression and nitric oxide (NO) secretion were significantly increased in CAFs secretome following radiotherapy. Culture of PDAC cells with conditioned media from radiotherapy-activated CAFs increased iNOS/NO signaling in tumor cells through NF-kB, which, in turn, elevated the release of inflammatory cytokines by the tumor cells. Increased NO after radiotherapy in PDAC contributed to an acidic microenvironment that was detectable using the radiolabeled pH (low) insertion peptide (pHLIP). In murine orthotopic PDAC models, pancreatic tumor growth was delayed when iNOS inhibition was combined with radiotherapy. These data show the important role that iNOS/NO signaling plays in the effectiveness of radiotherapy to treat PDAC tumors. Significance:Aradiolabeled pH-targeted peptide can be used as a PET imaging tool to assess therapy response within PDAC and blocking iNOS/NO signaling may improve radiotherapy outcomes.
AB - Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and the response of PDAC cells to radiotherapy are unknown. Using patient samples and orthotopic PDAC biological models, we showed that radiotherapy increased inducible nitric oxide synthase (iNOS) in the tumor tissues. Mechanistic in vitro studies showed that, although undetectable in radiotherapy-activated tumor cells, iNOS expression and nitric oxide (NO) secretion were significantly increased in CAFs secretome following radiotherapy. Culture of PDAC cells with conditioned media from radiotherapy-activated CAFs increased iNOS/NO signaling in tumor cells through NF-kB, which, in turn, elevated the release of inflammatory cytokines by the tumor cells. Increased NO after radiotherapy in PDAC contributed to an acidic microenvironment that was detectable using the radiolabeled pH (low) insertion peptide (pHLIP). In murine orthotopic PDAC models, pancreatic tumor growth was delayed when iNOS inhibition was combined with radiotherapy. These data show the important role that iNOS/NO signaling plays in the effectiveness of radiotherapy to treat PDAC tumors. Significance:Aradiolabeled pH-targeted peptide can be used as a PET imaging tool to assess therapy response within PDAC and blocking iNOS/NO signaling may improve radiotherapy outcomes.
UR - http://www.scopus.com/inward/record.url?scp=85083324561&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-2991
DO - 10.1158/0008-5472.CAN-19-2991
M3 - Article
C2 - 32086240
AN - SCOPUS:85083324561
SN - 0008-5472
VL - 80
SP - 1681
EP - 1692
JO - Cancer research
JF - Cancer research
IS - 8
ER -