Selective inhibition of stemness through EGFR/FOXA2/SOX9 axis reduces pancreatic cancer metastasis.

Autor: Kaushik G; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Seshacharyulu P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Rauth S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Nallasamy P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Rachagani S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Nimmakayala RK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Vengoji R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Mallya K; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Chirravuri-Venkata R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Singh AB; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Foster JM; Division of Surgical Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA., Ly QP; Division of Surgical Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA., Smith LM; Department of Biostatistics, UNMC, Omaha, NE, USA., Lele SM; Department of Pathology and Microbiology, UNMC, Omaha, NE, USA., Malafa MP; Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Jain M; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA., Ponnusamy MP; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. mpalanim@unmc.edu.; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA. mpalanim@unmc.edu., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. sbatra@unmc.edu.; Department of Pathology and Microbiology, UNMC, Omaha, NE, USA. sbatra@unmc.edu.; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA. sbatra@unmc.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2021 Jan; Vol. 40 (4), pp. 848-862. Date of Electronic Publication: 2020 Dec 07.
DOI: 10.1038/s41388-020-01564-w
Abstrakt: Pancreatic cancer (PC) is difficult to defeat due to mechanism (s) driving metastasis and drug resistance. Cancer stemness is a major challenging phenomenon associated with PC metastasis and limiting therapy efficacy. In this study, we evaluated the pre-clinical and clinical significance of eradicating pancreatic cancer stem cells (PCSC) and its components using a pan-EGFR inhibitor afatinib in combination with gemcitabine. Afatinib in combination with gemcitabine significantly reduced Kras G12D/+ ; Pdx-1 Cre (KC) (P < 0.01) and Kras G12D/+ ; p53 R172H/+ ; Pdx-1 Cre (KPC) (P < 0.05) derived mouse tumoroids and KPC-derived murine syngeneic cell line growth compared to gemcitabine/afatinib alone treatment. The drug combination also reduced PC xenograft tumor burden (P < 0.05) and the incidence of metastasis by affecting key stemness markers, as confirmed by co-localization studies. Moreover, the drug combination significantly decreases the growth of various PC patient-derived organoids (P < 0.001). We found that SOX9 is significantly overexpressed in high-grade PC tumors (P < 0.05) and in chemotherapy-treated patients compared to chemo-naïve patients (P < 0.05). These results were further validated using publicly available datasets. Moreover, afatinib alone or in combination with gemcitabine decreased stemness and tumorspheres by reducing phosphorylation of EGFR family proteins, ERK, FAK, and CSC markers. Mechanistically, afatinib treatment decreased CSC markers by downregulating SOX9 via FOXA2. Indeed, EGFR and FOXA2 depletion reduced SOX9 expression in PCSCs. Taken together, pan-EGFR inhibition by afatinib impedes PCSCs growth and metastasis via the EGFR/ERK/FOXA2/SOX9 axis. This novel mechanism of pan-EGFR inhibitor and its ability to eradicate CSC may serve as a tailor-made approach to enhance chemotherapeutic benefits in other cancer types.
Databáze: MEDLINE