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Updated: Jun 13, 2026
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis
Xin Wang1, Zvi Cramer1, Nicolae Adrian Leu1
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Abstract:
Metastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable. We develop a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. We conduct in vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model. We identify CTNNA1 and BCL2L13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. This study demonstrates proof of principle that large-scale genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of metastasis.
Insights
Researchers identified CTNNA1 and BCL2L13 as key suppressors of metastasis in colorectal cancer. Their loss promotes cancer cell spread and survival, highlighting new therapeutic targets for metastatic disease.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Metastatic outgrowth is a complex process involving multiple steps, from primary tumor cell detachment to distal site proliferation.
- Identifying genetic drivers of metastasis is challenging due to their potential variability compared to early oncogenesis drivers.
Purpose of the Study:
- To develop and apply a screening framework for identifying metastasis regulators.
- To discover novel metastasis-specific suppressors in colorectal adenocarcinoma using genetic screening.
Main Methods:
- Utilized CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma.
- Conducted in vitro screens for invasion and migration.
- Performed orthotopic, in vivo screens for metastasis in a syngeneic mouse model.
Main Results:
- Identified CTNNA1 (Cadherin 1) and BCL2L13 (BCL2 Like 13) as metastasis-specific suppressors.
- Demonstrated that loss of CTNNA1 enhances cell invasion and migration.
- Showed that loss of BCL2L13 promotes anchorage-independent survival and alters macrophage polarization.
Conclusions:
- CTNNA1 and BCL2L13 are novel regulators that specifically suppress metastasis without affecting primary tumor growth.
- Validated the utility of tumor-organoid models for large-scale in vivo genetic screening.
- Established a framework for identifying metastasis regulators with potential therapeutic implications.
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