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<p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor survival outcomes. Genomic analyses have identified distinct molecular subtypes in human PDAC with the quasimesenchymal/squamous/basal-like (QSB) subtype having the worst prognosis. However, no in vivo models exist for QSB subtypes. The epithelial–mesenchymal transition (EMT) transcription factor <i>TWIST1</i> is upregulated in QSB PDAC. Here we hypothesized that <i>TWIST1</i>-dependent plasticity is a key regulator of QSB PDAC subtype development. Non-negative matrix factorization (NMF) of human PDAC subtypes identified three NMF clusters. NMF1 was dominated by QSB subtypes, had the worst survival and exhibited high <i>TWIST1</i> expression. We generated a novel tetracycline-inducible autochthonous pancreas<i>-</i>specific <i>Kras</i><sup><i>G12D</i></sup><i>-Twist1</i> genetically engineered tumor mouse model (<i>Pdx1 promoter-Cre</i> (P); <i>LSL-Kras</i><sup><i>G12D</i></sup> (R); <i>Rosa26-LSL-rtTA-IRES-GFP</i> (G); <i>Twist1-tetO-Luc</i> (T)). PGRT mice showed accelerated pancreatic tumor development and decreased overall median survival compared with PGR (<i>Kras</i><sup><i>G12D</i></sup> alone) mice (4.6 months versus 9.7 months, <i>P</i> &lt; 0.0001). Histological analyses showed pancreatic tumor progression in PGRT toward the QSB subtype, exhibiting an EMT profile and squamous histology. <i>Twist1</i> induction resulted in increased metastases (9.52% PGR at 48 weeks versus 73.91% PGRT at 24 weeks, <i>P</i> &lt; 0.0001). PGRT tumors showed gene expression programs related to collagen content, EMT and cell movement, and were most concordant with human QSB PDAC subtypes and the squamoid single-cell subtype. Altogether, <i>Twist1</i> overexpression cooperated with <i>Kras</i><sup><i>G12D</i></sup> to drive PDAC development and metastatic progression, induced a fibrotic stroma associated with increased α-SMA<sup>+</sup> staining and mimicked the human QSB PDAC subtypes. This model opens perspectives to pursue the characterization of aggressive PDAC and develop therapeutic strategies.</p>

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Twist1 overexpression models an aggressive subtype of pancreatic ductal adenocarcinoma in vivo

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Muhammad Ajmal Khan,
  • Jinhee Chang,
  • Yang Song,
  • Amol C. Shetty,
  • Triet Nguyen,
  • Danielle N. Waters,
  • Dipanwita Dutta Chowdhury,
  • Elan Simms,
  • Aaron Chan,
  • Hwai Wei Tseng,
  • Christine Lam,
  • Priyanshi Patel,
  • Lucas T. Tran,
  • Jiayu Chen,
  • Jarey H. Wang,
  • Katriana Nugent,
  • Matthew Ballew,
  • Ghali Lemtiri-Chlieh,
  • Francesca Anna Carrieri,
  • Reem Malek,
  • Hailun Wang,
  • Noelle R. Jurcak Thielman,
  • Keyu Li,
  • Ryan J. Park,
  • William L. Hwang,
  • Lei Zheng,
  • Kathleen Gabrielson,
  • Phuoc T. Tran,
  • Audrey Lafargue

摘要

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor survival outcomes. Genomic analyses have identified distinct molecular subtypes in human PDAC with the quasimesenchymal/squamous/basal-like (QSB) subtype having the worst prognosis. However, no in vivo models exist for QSB subtypes. The epithelial–mesenchymal transition (EMT) transcription factor TWIST1 is upregulated in QSB PDAC. Here we hypothesized that TWIST1-dependent plasticity is a key regulator of QSB PDAC subtype development. Non-negative matrix factorization (NMF) of human PDAC subtypes identified three NMF clusters. NMF1 was dominated by QSB subtypes, had the worst survival and exhibited high TWIST1 expression. We generated a novel tetracycline-inducible autochthonous pancreas-specific KrasG12D-Twist1 genetically engineered tumor mouse model (Pdx1 promoter-Cre (P); LSL-KrasG12D (R); Rosa26-LSL-rtTA-IRES-GFP (G); Twist1-tetO-Luc (T)). PGRT mice showed accelerated pancreatic tumor development and decreased overall median survival compared with PGR (KrasG12D alone) mice (4.6 months versus 9.7 months, P < 0.0001). Histological analyses showed pancreatic tumor progression in PGRT toward the QSB subtype, exhibiting an EMT profile and squamous histology. Twist1 induction resulted in increased metastases (9.52% PGR at 48 weeks versus 73.91% PGRT at 24 weeks, P < 0.0001). PGRT tumors showed gene expression programs related to collagen content, EMT and cell movement, and were most concordant with human QSB PDAC subtypes and the squamoid single-cell subtype. Altogether, Twist1 overexpression cooperated with KrasG12D to drive PDAC development and metastatic progression, induced a fibrotic stroma associated with increased α-SMA+ staining and mimicked the human QSB PDAC subtypes. This model opens perspectives to pursue the characterization of aggressive PDAC and develop therapeutic strategies.