In vivo Mouse Models of Pancreatic Ductal Adenocarcinoma

Reyes, Carmen Mota; Gärtner, P; Rosenkranz, Laura; Grippo, Paul J.; Demir, Ihsan Ekin

doi:10.3998/panc.2021.13

Cited by 3 publications

(4 citation statements)

References 79 publications

(152 reference statements)

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“…However, therapy responses in allograft implantation models can depend on location [92] and used cell lines [93], which leads to interpretations of results being specific to the features of the cell line [94]. There is a multitude of different models used in preclinical PDAC research, ranging from chemically induced models to genetically engineered or implantation models [95,96]. Patient-derived xenograft models are considered a standard in preclinical oncology because the use of human cell lines in treating human cancers is a clear translational advantage [97].…”

Section: Discussionmentioning

confidence: 99%

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

Schulz,

Leitner,

Schreiber

et al. 2024

Cancers

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Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds.

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Section: Discussionmentioning

confidence: 99%

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

Schulz,

Leitner,

Schreiber

et al. 2024

Cancers

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“…A plethora of genetically engineered mouse models (GEMMs) of PDAC allow for investigation into different constituents of the TME, the role of different genes in cancer initiation and progression, and screening for therapeutic targets and resistance mechanisms in immunocompetent mice [26]. These models are based on the Cre/loxP-mediated activation of mutant KRAS (G12D/V) in combination with the inactivation of one or more tumor suppressor genes (e.g., p53, Tgfrb2, Smad4, Ink4a/Arf) driven by the Pdx-1 or P48 promoter expressed by exocrine pancreatic cells.…”

Section: Rationale For Immune Checkpoint Inhibition In Mpdacmentioning

confidence: 99%

“…These models are based on the Cre/loxP-mediated activation of mutant KRAS (G12D/V) in combination with the inactivation of one or more tumor suppressor genes (e.g., p53, Tgfrb2, Smad4, Ink4a/Arf) driven by the Pdx-1 or P48 promoter expressed by exocrine pancreatic cells. Depending on the inactivated tumor suppressor gene, these models recapitulate different characteristics of human PDAC [26].…”

Section: Rationale For Immune Checkpoint Inhibition In Mpdacmentioning

confidence: 99%

The Role of Immune Checkpoint Inhibitors in Metastatic Pancreatic Cancer: Current State and Outlook

Tran,

Özdemir,

Berger

2023

Pharmaceuticals

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, characterized by its aggressive tumor biology and poor prognosis. While immune checkpoint inhibitors (ICIs) play a major part in the treatment algorithm of various solid tumors, there is still no evidence of clinical benefit from ICI in patients with metastatic PDAC (mPDAC). This might be due to several reasons, such as the inherent low immunogenicity of pancreatic cancer, the dense stroma-rich tumor microenvironment that precludes an efficient migration of antitumoral effector T cells to the cancer cells, and the increased proportion of immunosuppressive immune cells, such as regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs), facilitating tumor growth and invasion. In this review, we provide an overview of the current state of ICIs in mPDAC, report on the biological rationale to implement ICIs into the treatment strategy of pancreatic cancer, and discuss preclinical studies and clinical trials in this field. Additionally, we shed light on the challenges of implementing ICIs into the treatment strategy of PDAC and discuss potential future directions.

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“…To understand the cellular and molecular mechanisms that contribute to KRAS G12D -mediated PDAC progression, genetically engineered mouse models (GEMMs) have been generated that allow spatial and temporal induction of KRAS G12D (4–9). A wide range of GEMMs exist, recapitulating the key features and mutations seen in human PDAC, including those allowing activation of KRAS G12D in combination with the inactivation of p16 , p53 or Smad4 , or with hereditary Brca1 and Brca2 mutations (4,10). While initial models focused on generating mutations in key genes during embryonic development, more recent GEMMs have focused on inducible, acinar-specific expression of KRAS G12D , which is more representative of the spontaneous mutations seen in patients (11–14).…”

Section: Introductionmentioning

confidence: 99%

Mouse models for pancreatic ductal adenocarcinoma are affected by the cre-driver used to promote KRAS^G12Dactivation

Mousavi,

Thompson,

Lau

et al. 2023

Preprint

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The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically modified mouse models that allow temporal and spatial activation of oncogenic KRAS (KRASG12D). The most commonly used model involves targeted insertion of acrerecombinase into thePtf1agene. However, this approach disrupts thePtf1agene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRASG12D). The goal of this study was to determine ifPtf1ahaploinsufficiency affected the acinar cell response to KRASG12Dbefore and after induction of pancreatic injury. We performed morphological and molecular analysis of three mouse lines that express a tamoxifen-induciblecrerecombinase to activate KRASG12Din acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes,Ptf1aandMist1/Bhlha15, or expressed within a BAC-derivedElastasetransgene. Up to two months after tamoxifen induction of KRASG12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in stark differences in tissue morphology between lines within seven days, which were maintained for at least five weeks after injury.Ptf1acreERTpancreata showed widespread PanIN lesions and fibrosis, while theMist1creERTandEla-creERTmodels showed reduced amounts of pre-neoplastic lesions. RNA-seq analysis prior to inducing injury suggestedPtf1acreERTandMist1creERTlines have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the lines. These findings suggest understanding the mechanisms underlying the differential response toKRASG12Dwill help in further defining the intrinsic KRAS-driven mechanisms of neoplasia initiation.

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In vivo Mouse Models of Pancreatic Ductal Adenocarcinoma

Cited by 3 publications

References 79 publications

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

The Role of Immune Checkpoint Inhibitors in Metastatic Pancreatic Cancer: Current State and Outlook

Mouse models for pancreatic ductal adenocarcinoma are affected by the cre-driver used to promote KRAS^G12Dactivation

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In vivo Mouse Models of Pancreatic Ductal Adenocarcinoma

Cited by 3 publications

References 79 publications

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

The Role of Immune Checkpoint Inhibitors in Metastatic Pancreatic Cancer: Current State and Outlook

Mouse models for pancreatic ductal adenocarcinoma are affected by the cre-driver used to promote KRASG12Dactivation

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Mouse models for pancreatic ductal adenocarcinoma are affected by the cre-driver used to promote KRAS^G12Dactivation