Choosing The Right Animal Model for Renal Cancer Research

Sobczuk, Paweł; Brodziak, Anna; Khan, Mohammed I.; Chhabra, Stuti; Fiedorowicz, Michał; Wełniak-Kamińska, Marlena; Synoradzki, Kamil; Bartnik, Ewa; Cudnoch-Jędrzejewska, Agnieszka; Czarnecka, Anna M.

doi:10.1016/j.tranon.2020.100745

Cited by 44 publications

(30 citation statements)

References 278 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also showed that aggressive ccRCC cells metastasized in zebrafish tails without genetic modification beforehand, and Plk1 inhibition prevented this metastatic spreading. Hence, the zebrafish model represents a relevant model to test new therapeutic drugs as recently reviewed 32 .…”

Section: Discussionmentioning

confidence: 99%

Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

et al. 2021

View full text Add to dashboard Cite

Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…A disease model is necessary to develop and test new therapies. However, because of the rarity of RMC, only two mouse models, both derived from primary renal tumor tissue, have been described to date (22)(23)(24). There are no reports of RMC mouse models developed from malignant pleural fluid.…”

Section: Discussionmentioning

confidence: 99%

Novel Patient Metastatic Pleural Effusion-Derived Xenograft Model of Renal Medullary Carcinoma Demonstrates Therapeutic Efficacy of Sunitinib

et al. 2021

View full text Add to dashboard Cite

BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p<0.001) and prolonged survival (p=0.004) compared to the vehicle control.ConclusionsA metastatic PE-derived RMC PDX model was established and shown to maintain histologic features of the patient cancer. Molecular integrity of the PDX models was well maintained between renal tumor and PE PDX as well as between two successive renal tumor PDX generations. Using the PE PDX model, sunitinib demonstrated therapeutic efficacy for RMC. This model can serve as a foundation for future mechanistic and therapeutic studies for primary and metastatic RMC.

show abstract

“…Despite of the crucial role of proper research platforms in understanding cancer pathophysiology and performing preclinical test of new therapeutic options, there is only an handful of renal cancer models , none of which showing consistent metastatic potential (21,22). In the present study, by engineering 9p21 loss in vivo, we generated the first somatic mosaic model of aggressive and metastatic RCC and captures the evolutionary features of human tumors.…”

Section: Discussionmentioning

confidence: 99%

9p21 Loss Defines the Evolutionary Patterns of Aggressive Renal Cell Carcinomas

Carbone

Huang

Perelli

et al. 2020

Preprint

View full text Add to dashboard Cite

Dedifferentiation and acquisition of chromosomal instability in renal cell carcinoma portends dismal prognosis and aggressive clinical behavior. However, the absence of reliable experimental models dramatically impacts the understanding of mechanisms underlying malignant progression. Here we established an in vivo genetic platform to rapidly generate somatic mosaic genetically engineerd immune-competent mouse models of renal tumors, recapitulating the genomic and phenotypic features of these malignancies. Leveraging somatic chromosomal engineering, we demonstrated that ablation of the murine locus syntenic to human 9p21 drives the rapid expansion of aggressive mesenchymal clones with prominent metastatic behavior, characterized by early emergence of chromosomal instability, whole-genome duplication, and conserved patterns of aneuploidy. This model of punctuated equilibrium provides a remarkable example of cross species convergent evolution.

show abstract

Choosing The Right Animal Model for Renal Cancer Research

Cited by 44 publications

References 278 publications

Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

Novel Patient Metastatic Pleural Effusion-Derived Xenograft Model of Renal Medullary Carcinoma Demonstrates Therapeutic Efficacy of Sunitinib

9p21 Loss Defines the Evolutionary Patterns of Aggressive Renal Cell Carcinomas

Contact Info

Product

Resources

About