Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine
George Zhang1, Yudan Chi1, Yi-Chieh Nancy Du2
1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine.
Abstract:
Metastatic cancer accounts for 90% of deaths in patients with solid tumors. There is an urgent need to better understand the drivers of cancer metastasis and to identify novel therapeutic targets. To investigate molecular events that drive the progression from primary cancer to metastasis, we have developed a bitransgenic mouse model, RIP-Tag; RIP-tva. In this mouse model, the rat insulin promoter (RIP) drives the expression of the SV40 T antigen (Tag) and the receptor for subgroup A avian leukosis virus (tva) in pancreatic β cells. The mice develop pancreatic neuroendocrine tumors with 100% penetrance through well-defined stages that are similar to human tumorigenesis, with stages including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. Because RIP-Tag; RIP-tva mice do not develop metastatic disease, genetic alterations that promote metastasis can be identified easily. Somatic gene transfer into tva-expressing, proliferating pancreatic β premalignant lesions is achieved through intracardiac injection of avian retroviruses harboring the desired genetic alteration. A titer of >1 x 108 infectious units per ml is considered appropriate for in vivo infection. In addition, avian retroviruses can infect cell lines derived from tumors in RIP-Tag; RIP-tva mice with high efficiency. The cell lines can also be used to characterize the metastatic factors. Here we demonstrate how to utilize this mouse model and cell lines to assess the functions of candidate genes in tumor metastasis.
Insights
Researchers developed a novel bitransgenic mouse model to study cancer metastasis. This model aids in identifying genetic drivers and therapeutic targets for metastatic solid tumors, crucial for improving patient survival.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Metastatic cancer is the primary cause of death in solid tumor patients.
- Understanding cancer metastasis drivers is critical for developing new therapies.
- Existing models often do not fully recapitulate metastatic progression.
Purpose of the Study:
- To develop and validate a bitransgenic mouse model for studying cancer metastasis.
- To identify genetic alterations that promote the transition from primary tumors to metastasis.
- To establish a platform for assessing candidate genes involved in tumor metastasis.
Main Methods:
- Development of the RIP-Tag; RIP-tva bitransgenic mouse model expressing SV40 T antigen and TVA receptor in pancreatic beta cells.
- Induction of pancreatic neuroendocrine tumors with defined stages mirroring human tumorigenesis.
- Somatic gene transfer via intracardiac injection of avian retroviruses into premalignant lesions to study metastatic drivers.
- Utilizing derived cell lines for efficient in vitro characterization of metastatic factors.
Main Results:
- The RIP-Tag; RIP-tva model reliably develops pancreatic neuroendocrine tumors with stages including hyperplasia, angiogenesis, adenoma, and invasive carcinoma.
- The model does not spontaneously develop metastatic disease, facilitating the identification of metastasis-promoting genetic alterations.
- Avian retroviruses efficiently infect both in vivo lesions and derived cell lines for genetic manipulation.
Conclusions:
- The RIP-Tag; RIP-tva mouse model is a powerful tool for investigating the molecular mechanisms of cancer metastasis.
- This model and its associated cell lines provide a robust platform for discovering novel therapeutic targets for metastatic disease.
- The methodology allows for the functional assessment of candidate genes in the context of tumor progression and metastasis.
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