Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.

By S. Hingorani, Lifu Wang, A. Multani, C. Combs, T. Deramaudt, R. Hruban, A. Rustgi, Sandy Chang, D. Tuveson. Cancer Cell, 2005

2,447 citations recorded by the source corpus.

To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease. The primary carcinomas and metastases demonstrate a high degree of genomic instability manifested by nonreciprocal translocations without obvious telomere erosion-hallmarks of human carcinomas not typically observed in mice. No mutations were discovered in other cardinal tumor suppressor gene pathways, which, together with previous results, suggests that there are distinct genetic pathways to PDA with different biological behaviors. These findings have clear implications for understanding mechanisms of disease pathogenesis, and for the development of detection and targeted treatment strategies.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5e3c684291a0e54ef73203cafd85b43182167166

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Oncology

Citations in the corpus

IL-1-induced JAK/STAT signaling is antagonized by TGF-β to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. (2018, background): “KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre) mice were previously described (18).”
Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, positive): “To better define the cellular and molecular basis of tumor immune variation, we employed an autochthonous mouse model of PDA (KPC) that recapitulatesmajor features of the human disease, includingmutated Kras and p53 (Hingorani et al., 2005; Rhim et al., 2012).”
The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression (2018, neutral): “A quintessential example of this in murine modeling of cancer is the variable tumor phenotype in KPC mice (15).”
Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer (2013, methodology): “The generation of KPC and FAP-DTR BAC transgenic mice has been described previously (9, 10).”
Tumor-stroma interactions in pancreatic ductal adenocarcinoma (2007, background): “However, the expression of Sonic hedgehog and E-cadherin was present in both preinvasive and invasive lesions that were moderately well differentiated but not in poorly differentiated lesions (34).”
Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. (2006, background): “…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).”
ATP citrate lyase inhibition can suppress tumor cell growth. (2005, background): “ground (Figure 8B) (Hingorani et al., 2005) and manifesting preinvasive or invasive pancreatic ductal adenocarcinoma, respectively.”
Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer (2010, methodology): “Targeting endogenous expression of Kras and p53 to the mouse pancreas (using Cre-Lox technology), via the Pdx1 pancreatic progenitor cell gene promoter, results in the formation of preinvasive PanIN lesions that develop into invasive and metastatic pancreatic cancer reminiscent of the human disease,”
DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. (2009, background): “This finding is reminiscent of epithelialmesenchymal transition (EMT), a feature well described in a variety of human tumors and in mouse models of pancreatic carcinoma.(34,35) High grade features were not correlated with stage at initial diagnosis nor any other clinicopathologic features, and sugge”
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma (2016, positive): “KPC (LSL-Kras; LSL-Trp53; Pdx1-Cre) mice carry a pancreas-specific Trp53 mutation alongside an initiating mutation in Kras, and develop invasive, metastatic tumors that exhibit an extensive stroma (Hingorani et al., 2005) (Figure S2A) with significant collagen deposition (visualized by picrosirius r”