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Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting.

Publication ,  Journal Article
Cheung, PF; Neff, F; Neander, C; Bazarna, A; Savvatakis, K; Liffers, S-T; Althoff, K; Lee, C-L; Moding, EJ; Kirsch, DG; Saur, D; Bazhin, AV ...
Published in: Cancer Res
September 1, 2018

Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes.Significance: This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. Cancer Res; 78(17); 4997-5010. ©2018 AACR.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 1, 2018

Volume

78

Issue

17

Start / End Page

4997 / 5010

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Microenvironment
  • Trans-Activators
  • Signal Transduction
  • Receptors, Notch
  • Proto-Oncogene Proteins p21(ras)
  • Oncology & Carcinogenesis
  • Myeloid Cells
  • Mice, Transgenic
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Cheung, P. F., Neff, F., Neander, C., Bazarna, A., Savvatakis, K., Liffers, S.-T., … Siveke, J. T. (2018). Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting. Cancer Res, 78(17), 4997–5010. https://doi.org/10.1158/0008-5472.CAN-18-0052
Cheung, Phyllis F., Florian Neff, Christian Neander, Anna Bazarna, Konstantinos Savvatakis, Sven-Thorsten Liffers, Kristina Althoff, et al. “Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting.Cancer Res 78, no. 17 (September 1, 2018): 4997–5010. https://doi.org/10.1158/0008-5472.CAN-18-0052.
Cheung PF, Neff F, Neander C, Bazarna A, Savvatakis K, Liffers S-T, et al. Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting. Cancer Res. 2018 Sep 1;78(17):4997–5010.
Cheung, Phyllis F., et al. “Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting.Cancer Res, vol. 78, no. 17, Sept. 2018, pp. 4997–5010. Pubmed, doi:10.1158/0008-5472.CAN-18-0052.
Cheung PF, Neff F, Neander C, Bazarna A, Savvatakis K, Liffers S-T, Althoff K, Lee C-L, Moding EJ, Kirsch DG, Saur D, Bazhin AV, Trajkovic-Arsic M, Heikenwalder MF, Siveke JT. Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting. Cancer Res. 2018 Sep 1;78(17):4997–5010.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 1, 2018

Volume

78

Issue

17

Start / End Page

4997 / 5010

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Microenvironment
  • Trans-Activators
  • Signal Transduction
  • Receptors, Notch
  • Proto-Oncogene Proteins p21(ras)
  • Oncology & Carcinogenesis
  • Myeloid Cells
  • Mice, Transgenic
  • Mice