Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.

By A. Aguirre, N. Bardeesy, M. Sinha, L. Lopez, D. Tuveson, J. Horner, M. Redston, R. DePinho. Genes & Development, 2003

1,048 citations recorded by the source corpus.

Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of KrasG12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, KrasG12D expression and Ink4a/Arf deficiency resulted in an earlier appearance of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of these tumors bears striking resemblance to the human disease, possessing a proliferative stromal component and ductal lesions with a propensity to advance to a poorly differentiated state. These findings in the mouse provide experimental support for the widely accepted model of human pancreatic adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the INK4A/ARF tumor suppressors function to constrain the malignant conversion of these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/1e429c1d26b4c6cade20a185599e8739d84d54f0

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In Molecular Biology

1. R. DePinho
2. D. Hanahan
3. Hans Clevers
4. N. Bardeesy
5. D. Tuveson
6. Alec C. Kimmelman
7. R. Vries
8. T. Jacks

In Oncology

1. D. Hanahan
2. Hans Clevers
3. D. Tuveson
4. Alec C. Kimmelman
5. Shizuo Akira
6. F. Balkwill
7. T. Jacks
8. S. Rose‐John

In Surgery

1. Hans Clevers
2. D. Hanahan
3. S. Rose‐John
4. Carol S. Lim
5. Alec C. Kimmelman
6. Shizuo Akira

Citations in the corpus

• Guidelines for the welfare and use of animals in cancer research (2010, background): “…K-rasG12D+Ink4a/Arf deficiency or combined withTrp53R172H Metastatic lung cancer Metastatic pancreatic cancer (Johnson et al, 2001) (Aguirre et al, 2003; Hingorani et al, 2005) AML1/ETO or MLL fusion proteins AML AML (Zuber et al, 2009) MYCN Neuroblastoma, Rhabdomyosarcoma,…”
• EMT and dissemination precede pancreatic tumor formation (2012, background): “Inflammation Promotes EMT, Invasiveness, and Dissemination The emergence of PanIN lesions is associated with the appearance of an inflammatory stroma characterized by activated fibroblasts andmyeloid-derived cells (Aguirre et al., 2003; Clark et al., 2007).”
• Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (2014, positive): “Immunohistochemical (IHC) analysis was performed as described earlier (Aguirre et al., 2003).”
• Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Diminished Survival (2014, neutral): “…16, 2014 ª2014 Elsevier Inc. stromal reaction in PDAC, a defining feature of this carcinoma, which accounts for the majority of the tumor tissue volume (Aguirre et al., 2003; Bardeesy et al., 2006a, 2006b; Gidekel Friedlander et al., 2009; Hingorani et al., 2003, 2005; Hruban et al., 2007; Ijichi…”
• Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. (2007, background): “Most models involve expression of K-Ras oncogenes (Aguirre et al., 2003; Brembeck et al., 2003; Grippo et al., 2003; Hingorani et al., 2003; Quaife et al., 1987; Tuveson et al., 2006), although transgenic expression of other oncogenes such as polyoma middle T and growth-promoting molecules, includin”
• Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. (2003, background): “…the LSL-KRASG12D mice Revised: November 26, 2003described here, it has recently been shown that pancreatic exPublished: December 10, 2003pression of oncogenic KRAS in the context of INK4a/ARF deficiency results in PDA with very short latency and high pene- References trance (Aguirre et al., 2003).”
• Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression and improves chemotherapeutic responses (2012, neutral): “Tg (17, 18) and p48-CRE/LSL-KrasG12D/INK4a (18, 19) mice, respectively.”
• Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. (2011, background): “(Trp53, Ink4A/Arf) in genetically engineered mice (GEM) recapitulates PanIN initiation and progression to pancreatic cancer (PC), similar to the clinical pathology (Aguirre et al., 2003; Guerra et al., 2007; Hingorani et al., 2003, 2005; Kelly et al., 2008).”
• Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. (2005, background): “By comparison, LSL-KrasG12D/+; Ink4a/Arf(flox/flox);Pdx-1-Cre animals (Aguirre et al., 2003) have a greatly curtailed median survival of approximately 8 weeks, develop primarily locally invasive disease, and show a prominent spindle cell or sarcomatoid histology, a rare phenotype in human…”
• Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. (2006, methodology): “…locus (encoding both p16INK4A and p19ARF), or of p53, does not induce pancreatic neoplasia; however, concurrent KrasG12D expression and inactivation of Ink4a/Arf or p53 drives the development of advanced PDAC with short latency (Aguirre et al. 2003; Hingorani et al. 2005; Bardeesy et al. 2006).”
• KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, background): “2005), Cdkn2a (Aguirre et al. 2003; Bardeesy et al. 2006), or Smad4 (Kojima et al.”
• Tumor-stroma interactions in pancreatic ductal adenocarcinoma (2007, background): “However, lung and liver metastases were rarely observed in these mice (33), indicating that directed activation of an oncogene and loss of a tumor suppressor in a genetic mouse model of PDA may not be a true reflection of human PDA, which may be due to species-specific gene expression and differenti”