scholarly journals Mouse models of cancers: opportunities to address heterogeneity of human cancer and evaluate therapeutic strategies

2010 ◽  
Vol 88 (11) ◽  
pp. 1095-1100 ◽  
Author(s):  
Eran R. Andrechek ◽  
Joseph R. Nevins
Keyword(s):  
Mouse Models ◽  
Human Cancer ◽  
Therapeutic Strategies

scholarly journals Investigating Tumor Heterogeneity in Mouse Models

2020 ◽  
Vol 4 (1) ◽  
pp. 99-119 ◽  
Author(s):  
Tuomas Tammela ◽  
Julien Sage
Keyword(s):  
Mouse Models ◽  
Tumor Heterogeneity ◽  
Stromal Cell ◽  
Human Cancer ◽  
Therapeutic Strategies ◽  
Clinical Implications ◽  
Epigenetic Alterations ◽  
Cancer Treatments ◽  
Extrinsic Factors ◽  
Major Barrier

Cancer arises from a single cell through a series of acquired mutations and epigenetic alterations. Tumors gradually develop into a complex tissue comprised of phenotypically heterogeneous cancer cell populations, as well as noncancer cells that make up the tumor microenvironment. The phenotype, or state, of each cancer and stromal cell is influenced by a plethora of cell-intrinsic and cell-extrinsic factors. The diversity of these cellular states promotes tumor progression, enables metastasis, and poses a challenge for effective cancer treatments. Thus, the identification of strategies for the therapeutic manipulation of tumor heterogeneity would have significant clinical implications. A major barrier in the field is the difficulty in functionally investigating heterogeneity in tumors in cancer patients. Here we review how mouse models of human cancer can be leveraged to interrogate tumor heterogeneity and to help design better therapeutic strategies.

Therapeutic Strategies for Targeting BRAF in Human Cancer

2007 ◽  
Vol 2 (2) ◽  
pp. 121-134 ◽  
Author(s):  
Christine Pratilas ◽  
David Solit
Keyword(s):  
Human Cancer ◽  
Therapeutic Strategies

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

scholarly journals Mouse models of human cancer and the need for more translational research

2008 ◽  
Author(s):  
Martin Fenner
Keyword(s):  
Mouse Model ◽  
Translational Research ◽  
Synovial Sarcoma ◽  
Mouse Models ◽  
Human Disease ◽  
Human Cancer ◽  
Neuropsychiatric Disorders ◽  
International Congress

One of the opening lectures this Saturday of the International Congress of Genetics was held by Mario Capecchi. His talked was entitled Modeling human disease in the mouse: from cancer to neuropsychiatric disorders. In the first half he described his mouse model of synovial sarcoma. ...

scholarly journals Mouse models for BRAF-induced cancers

2007 ◽  
Vol 35 (5) ◽  
pp. 1329-1333 ◽  
Author(s):  
C. Pritchard ◽  
L. Carragher ◽  
V. Aldridge ◽  
S. Giblett ◽  
H. Jin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Models ◽  
Human Cancer ◽  
Cre Recombinase ◽  
Genetically Engineered ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Single Nucleotide Change

Oncogenic mutations in the BRAF gene are detected in ∼7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine→glutamate mutation at residue 600 (V600EBRAF). In cells cultured in vitro, V600EBRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that V600EBRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.

Abstract 435: Mouse models of human cancer

2020 ◽  
Author(s):  
Carol J. Bult ◽  
Debra M. Krupke ◽  
Steven B. Neuhauser ◽  
Joel E. Richardson ◽  
John P. Sundberg
Keyword(s):  
Mouse Models ◽  
Human Cancer

Counterpoint: In Some AMLs, Stem Cells are More Mature and Present at High Frequency.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-35-SCI-35
Author(s):  
Michael L. Cleary
Keyword(s):  
Stem Cells ◽  
Mouse Models ◽  
Conflicts Of Interest ◽  
Human Cancer ◽  
Hierarchical Organization ◽  
Leukemia Stem Cells ◽  
Aberrant Expression ◽  
Myeloid Lineage ◽  
Hematopoietic Stem ◽  
Current Paradigm

Abstract Abstract SCI-35 Leukemia stem cells (LSCs) are responsible for sustaining and propagating malignant disease and, therefore, are promising targets for therapy. The current paradigm for LSC frequency, maturation and hierarchical organization is primarily based on transplantation studies in xenograft mouse models. To circumvent potential limitations of this experimental approach, investigators have recently employed syngeneic mouse models to study LSCs. In a mouse model of AML initiated by MLL oncogenes, which are associated with the FAB-M4 or M5 subtypes of human AML, LSCs are remarkably frequent, accounting for up to one-quarter of malignant myeloid cells at late-stage disease. Even in this syngeneic setting, however, transplant assays alone markedly underestimate LSC frequency due to poor engraftment efficiency. LSCs are organized in a phenotypic and functional hierarchy, and express myeloid lineage-specific antigens, placing them downstream of the known hematopoietic progenitor compartments. Thus, LSCs in this model are not synonymous with normal upstream progenitors that are targeted for leukemia initiation, but rather constitute myeloid lineage cells that have acquired an aberrant self-renewal program as well as other biologic features of hematopoietic stem cells. Gene expression profiling confirms the downstream myeloid character of LSCs in this model, and further demonstrates the aberrant expression of a stem cell associated transcriptional subprogram. However, LSC maintenance in the self-renewing compartment of AML employs a global transcriptional program more akin to embryonic rather than adult stem cells. Expression of LSC maintenance program genes is enriched in poor prognosis human malignancies, suggesting that the frequency of aberrantly self-renewing progenitor-like cancer stem cells may be linked to prognosis in human cancer. Consistent with this possibility, LSC frequencies in different syngeneic models of Hox-associated AML can vary over three orders of magnitude, depending on the particular initiating oncogene and expression levels of Hox pathway co-regulators, and correlate with leukemia biology. Studies in a human cord blood cell transduction/transplantation model of AML further support the downstream character of MLL LSCs. These findings prompt a revision of the current paradigm that AML leukemia stem cells are always rare and solely located within the most immature bone marrow progenitor compartments. The fact that LSCs can be more analogous to precursors and employ ESC-like genetic programs for their maintenance, may allow for their selective therapeutic targeting that spares HSCs required for hematopoiesis. Disclosures No relevant conflicts of interest to declare.

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