TY - JOUR
T1 - Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis
AU - Bhatia, Rakesh
AU - Siddiqui, Jawed Akhtar
AU - Ganguly, Koelina
AU - Thompson, Christopher M.
AU - Cannon, Andrew
AU - Aithal, Abhijit
AU - Perumal, Naveenkumar
AU - Maurya, Shailendra K.
AU - Li, Xiaoqi
AU - Cox, Jesse L.
AU - Gurumurthy, Channabasavaiah B.
AU - Rachagani, Satyanarayana
AU - Jain, Maneesh
AU - Nasser, Mohd Wasim
AU - Batra, Surinder K.
AU - Kumar, Sushil
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/3/3
Y1 - 2023/3/3
N2 - Mucin4 (MUC4) appears early during pancreatic intraepithelial neoplasia-1 (PanIN1), coinciding with the expression of epidermal growth factor receptor-1 (EGFR). The EGFR signaling is required for the onset of Kras-driven pancreatic ductal adenocarcinoma (PDAC); however, the players and mechanisms involved in sustained EGFR signaling in early PanIN lesions remain elusive. We generated a unique Esai-CRISPR-based Muc4 conditional knockout murine model to evaluate its effect on PDAC pathology. The Muc4 depletion in the autochthonous murine model carrying K-ras and p53 mutations (K-rasG12D; TP53R172H; Pdx-1cre, KPC) to generate the KPCM4−/− murine model showed a significant delay in the PanIN lesion formation with a significant reduction (p < 0.01) in EGFR (Y1068) and ERK1/2 (T202/Y204) phosphorylation. Further, a significant decrease (p < 0.01) in Sox9 expression in PanIN lesions of KPCM4−/− mice suggested the impairment of acinar-to-ductal metaplasia in Muc4-depleted cells. The biochemical analyses demonstrated that MUC4, through its juxtamembrane EGF-like domains, interacts with the EGFR ectodomain, and its cytoplasmic tail prevents EGFR ubiquitination and subsequent proteasomal degradation upon ligand stimulation, leading to sustained downstream oncogenic signaling. Targeting the MUC4 and EGFR interacting interface provides a promising strategy to improve the efficacy of EGFR-targeted therapies in PDAC and other MUC4-expressing malignancies.
AB - Mucin4 (MUC4) appears early during pancreatic intraepithelial neoplasia-1 (PanIN1), coinciding with the expression of epidermal growth factor receptor-1 (EGFR). The EGFR signaling is required for the onset of Kras-driven pancreatic ductal adenocarcinoma (PDAC); however, the players and mechanisms involved in sustained EGFR signaling in early PanIN lesions remain elusive. We generated a unique Esai-CRISPR-based Muc4 conditional knockout murine model to evaluate its effect on PDAC pathology. The Muc4 depletion in the autochthonous murine model carrying K-ras and p53 mutations (K-rasG12D; TP53R172H; Pdx-1cre, KPC) to generate the KPCM4−/− murine model showed a significant delay in the PanIN lesion formation with a significant reduction (p < 0.01) in EGFR (Y1068) and ERK1/2 (T202/Y204) phosphorylation. Further, a significant decrease (p < 0.01) in Sox9 expression in PanIN lesions of KPCM4−/− mice suggested the impairment of acinar-to-ductal metaplasia in Muc4-depleted cells. The biochemical analyses demonstrated that MUC4, through its juxtamembrane EGF-like domains, interacts with the EGFR ectodomain, and its cytoplasmic tail prevents EGFR ubiquitination and subsequent proteasomal degradation upon ligand stimulation, leading to sustained downstream oncogenic signaling. Targeting the MUC4 and EGFR interacting interface provides a promising strategy to improve the efficacy of EGFR-targeted therapies in PDAC and other MUC4-expressing malignancies.
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U2 - 10.1038/s41388-022-02587-1
DO - 10.1038/s41388-022-02587-1
M3 - Article
C2 - 36624189
AN - SCOPUS:85145849560
SN - 0950-9232
VL - 42
SP - 759
EP - 770
JO - Oncogene
JF - Oncogene
IS - 10
ER -