| Autor: |
Koetsu Inoue, Daniel H. Schanne, Aya Matsui, Pinji Lei, Sebastian Klein, Shuichi Aoki, Hajime Taniguchi, Hiroto Kikuchi, Jiang Chen, Zelong Liu, Shengdar Q. Tsai, Tyge CE Schmidt, Masaaki Iwasaki, Glenn Geidel, Alexander Koch, Peigen Huang, Dai Fukumura, Toshihiro Shioda, Lance L. Munn, Carlos Fernandez-del Castillo, Theodore S. Hong, Rakesh K. Jain, Andrew Liss, Nabeel Bardeesy, Dan G. Duda |
| Rok vydání: |
2022 |
| Popis: |
Activating mutations of KRAS play critical roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence indicates that distinct KRAS alleles associate with different prognoses, but the underlying mechanisms are not known. We established isogenic KRAS mutants (KRASG12D, KRASG12V, and KRASWT) using a KRASG12R patient-derived PDAC cell line by CRISPR/Cas9 knock-in. We used these isogenic cell lines, a collection of characterized human PDAC patient-derived cell lines, and murine PDAC models to study the role of these KRAS alleles in vitro and in vivo. We verified that the growth of KRASG12D cells is more aggressive compared to KRASG12V isogenic cells in vitro and in vivo using orthotopic mouse models. Signal transducer and activator of transcription (STAT) activation was the most significant difference between KRASG12D and KRASG12V isogenic PDACs. Furthermore, activation of interferon-alpha (IFNA)/IFNA receptor (IFNAR)1/STAT3 signaling in the cancer cells mediated the more aggressive phenotype of KRASG12D PDACs. Conversely, inhibition of IFNAR1 in patient-derived PDAC cells suppressed tumor growth. Finally, IFNAR1 blockade was also effective in murine PDAC models and induced a significant increase in survival when combined with immune checkpoint blockade therapy. We conclude that the IFNA pathway and IFNAR1/STAT3 axis contribute to a more aggressive tumor progression in human KRASG12D PDACs and that IFNAR1 inhibition is a potential therapeutic target for overcoming resistance to immunotherapy in PDAC.One Sentence SummaryIFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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