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

Hingorani, Sunil R.; Wang, Lifu; Multani, Asha S.; Combs, Chelsea; Deramaudt, Therese B.; Hruban, Ralph H.; Rustgi, Anil K.; Chang, Sandy; Tuveson, David A.

doi:10.1016/j.ccr.2005.04.023

Cited by 2,609Pancreatic and Hepatic Oncology ResearchCancer Genomics and DiagnosticsCancer-related Molecular Pathways

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

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Hingorani, Sunil R., Wang, Lifu, Multani, Asha S., Combs, Chelsea, Deramaudt, Therese B., Hruban, Ralph H., Rustgi, Anil K., Chang, Sandy +1 more·2005·Cancer Cell

DOI 10.1016/j.ccr.2005.04.023

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Abstract

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.

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The Mm1 cell line is derived from a liver metastasis of the autochthonous KPC model of pancreatic cancer, which recapitulates the low immunogenicity and immunotherapy responsiveness of the human pancreatic cancer.
“which is derived from a liver metastasis of the autochthonous KPC model of pancreatic cancer,73 which recapitulates the low immunogenicity and immunotherapy responsiveness of the human pancreatic cancer.”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [73]
GEMMs combining Kras mutation with inactivation of Cdkn2a and Tp53, or with inactivation of TGFβ-SMAD4 signaling, develop invasive and metastatic PDAC, validating these tumor suppressor pathways in PDAC progression.
“GEMMs with compound mutations that combine Kras mutation with the inactivation of tumor suppressor genes Cdkn2a and Tp53, or with the inactivation of the TGFβ-SMAD4 signaling pathway in the pancreas develop invasive and metastatic PDAC (74–76), thus validating the role of these tumor suppressor pathways in PDAC progression (4).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [75]
Combined expression of oncogenic Kras with deletion or loss of function of Trp53, Cdkn2a, or Smad4 in mouse pancreas readily leads to invasive PDAC.
“combined expression of oncogenic Kras coupled with the deletion or loss of function of Trp53, Cdkn2a, or Smad4 in the pancreas of mice readily leads to invasive PDAC29–32.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [30]
Altered p53 function has multiple tumor-promoting effects on neoplastic cells, including increased genomic instability, reprogrammed cellular metabolism, and enhanced metastatic propensity.
“altered p53 function has a multitude of tumor-promoting effects on neoplastic cells, including increased genomic instability30, reprogrammed cellular metabolism57,58, and enhanced metastatic propensity59.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [30]

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Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
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KrasG12D and Smad4/Dpc4 Haploinsufficiency Cooperate to Induce Mucinous Cystic Neoplasms and Invasive Adenocarcinoma of the Pancreas
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Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer
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α-Ketoglutarate links p53 to cell fate during tumour suppression
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Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution
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Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer
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Clinical Significance of the Genetic Landscape of Pancreatic Cancer and Implications for Identification of Potential Long-term Survivors
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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer
Dilly, J., Hoffman, M. T., Abbassi, L., Li, Z., Paradiso, F., Parent, B. D., Hennessey, C. J., Jordan, A. C., Morgado, M., Dasgupta, S., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0177 · Cited by 276 · see citing works
“After evaluating features of response and resistance to MRTX1133 in vitro , we sought to investigate the efficacy of KRAS G12D inhibition in the immunocompetent, autochtho-nous KPC ( Kras LSL-G12D/ + ; Trp53 LSL-R172H/ + ; p48-Cre ) genetically engineered mouse model (GEMM) of PDAC (49).”
Background
CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Vennin, C., Mélénec, P., Rouet, R., Nobis, M., Cazet, A. S., Murphy, K. J., Herrmann, D., Reed, D. A., Lucas, M. C., Warren, S. C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10968-6 · Cited by 268 · see citing works
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Molecular genetics of pancreatic intraepithelial neoplasia
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SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
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Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
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Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma
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KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells
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BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity
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NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma
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Authors: Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A.
Affiliations: Abramson Cancer Center (US)
The University of Texas MD Anderson Cancer Center (US)
Johns Hopkins University (US)
University of Pennsylvania (US)
Corresponding author: Hingorani, Sunil R.
Tuveson, David A.
ORCID: Hingorani, Sunil R.
Wang, Lifu
Multani, Asha S.
Hruban, Ralph H.
Rustgi, Anil K.
Chang, Sandy
Tuveson, David A.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2005-05
Volume: 7
Issue: 5
Pages: 469-483
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2005.04.023
OpenAlex: W1992995822
Cited by: 2,609
References: 61
Citations by year: 2026: 128 · 2025: 127 · 2024: 208 · 2023: 213 · 2022: 171 · 2021: 217 · 2020: 180 · 2019: 176 · 2018: 164 · 2017: 151 · 2016: 146 · 2015: 128 · 2014: 112 · 2013: 116 · 2012: 77
FWCI: 18.03
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3035 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (K08AG001019)
National Cancer Institute (R25-CA87812, P50CA-62924, U01CA084291, R25CA087812, R01CA101973, P50CA062924)
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK60694, R01DK060694)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: pancreatic ductal adenocarcinoma, KRAS G12D, chromosomal instability, non-reciprocal translocation, metastasis, tumor suppressor, oncogene cooperation, mouse model, pancreatic carcinogenesis, genomic instability
MeSH terms: Animals, Chromosome Aberrations, Gene Expression Regulation, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Mutant Strains, Mice, Transgenic, Neoplasm Metastasis, Translocation, Genetic, Gene Rearrangement, Trans-Activators, Cadherins, Gene Expression, Survival Analysis, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Telomere, Centrosome, Homeodomain Proteins, Disease Progression, ras Proteins, Oncogene Proteins v-erbB, Integrases, Mutation, Missense, Cytogenetic Analysis, Carcinoma, Pancreatic Ductal, Chromosomal Instability, Mice

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

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