A recent study published in Genes & Diseases by researchers from Case Western Reserve University, University Hospitals Cleveland Medical Center and Translational Hematology & Oncology Research, Cleveland Clinic introduces the first multiplexed in vivo CRISPR/Cas9 model aimed at defining the functional consequences of TBX2 subfamily loss in KRAS-driven lung cancer.
Using TuBa-seq, a highly quantitative tumor-barcoding and sequencing platform, the research team simultaneously assessed the roles of Tbx2, Tbx3, Tbx4, Tbx5, Egr1, Chd2, Tnfaip3, and Atf3 across thousands of genetically edited tumors in KrasLSL-G12D; Rosa26LSL-Cas9 (KC) mice. This approach enabled precise measurement of tumor initiation, early growth dynamics, and advanced progression within the same animal model.
The results revealed strikingly diverse functions among these genes. Chd2 loss consistently impaired tumor initiation and reduced overall tumor size, suggesting a growth-suppressive role under KRAS-mutant conditions. In contrast, Tnfaip3 knockout significantly enhanced early tumor expansion, in line with its known involvement in inflammatory regulation. Tbx2 deletion demonstrated a stage-specific pattern, promoting early tumor initiation but reducing average growth, while still contributing to the formation of some of the largest tumors at later stages. Meanwhile, loss of Tbx3, Tbx4, Tbx5, or Atf3 caused only minimal alterations in tumor burden.
Remarkably, Egr1 emerged as the most potent tumor suppressor. Its deletion resulted in an approximately fivefold increase in tumor size by 20 weeks—exceeding even the effect of Rb1 loss. Transcriptomic profiling of Egr1-deficient tumors revealed extensive immune dysregulation, including heightened inflammatory signaling, shifts in leukocyte activation pathways, and significant upregulation of T-cell exhaustion markers such as PD-1, LAG-3, and CTLA-4. These findings indicate that Egr1 limits tumor progression partly by regulating the immune microenvironment.
Notably, EGR1 knockout in human KRAS-mutant lung cancer cell lines did not enhance proliferation, indicating that its tumor-suppressive effects are mediated by in vivo immune interactions rather than intrinsic cell-intrinsic growth mechanisms.
Together, this study demonstrates the complex, context-dependent roles of the TBX2 subfamily in lung cancer and identifies Egr1 as a central regulator of KRAS-driven tumor progression and immune modulation. By applying a multiplexed in vivo CRISPR approach, this study provides a powerful framework for uncovering hidden tumor-suppressor functions and highlights Egr1 as a promising candidate for future biomarker development and therapeutic exploration.
Reference
Title of Original Paper : In vivo multiplexed modeling reveals diverse roles of the TBX2 subfamily and Egr1 in Ras-driven lung adenocarcinoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101840
License type: CC BY-NC-ND
Funding Information: The US National Institutes of Health (No. R01CA271540, No. R00CA226506; No. R01CA196643, No. R01CA264320, No. R01CA260629, No. P50CA150964, No. P30 CA043703)
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