In vivo multiplexed modeling reveals diverse roles of the TBX2 subfamily and Egr1 in Kras-driven lung adenocarcinomaOA
The TBX2 subfamily of T-box transcription factors(e.g.,Tbx2,Tbx3,Tbx4,Tbx5)plays an essential role in lung development,Down-regulation of these genes in human lung adenocarcinoma suggests that these genes may be tumor-suppressive;however,because down-regulation appears to occur primarily via epigenetic change,it remains unclear if these changes causally drive tumor progression or are merely the consequence of upstream events,Herein,we developed the first multiplexed mouse model to study the impact of TBX2 subfamily loss,alongside associated signaling genes(Egr1,Chd2,Tnfaip3a,and Atf3)in Ras-driven lung cancer,Using tumor-barcoding with high-throughput barcode sequencing(TuBa-seq),a high-throughput tumor-barcoding system,we quantified the growth effects of these knockouts during early and late tumorigenesis,Chd2 knockout suppressed both tumor initiation and progression,whereas Tnfaip3 knockout enhanced tumor initiation and overall tumor growth,Tbx2 loss showed stage-specific effects on tumor development,Notably,Egr1 emerged as a strong tumor suppressor and its knockout resulted in approximately a fivefold increase in tumor size at 20 weeks(two-sample t-test,p<0.05),exceeding the impact observed with Rb1 loss,Transcriptomic analyses of Egr1-deficient tumors suggested immune dysregulation,including heightened inflammation and potential markers of T cell exhaustion in the tumor microenvironment,These findings indicate that Egr1 may play a role in suppressing tumor growth through modulating immune dynamics,offering new insights into the interplay between tumor progression and immune regulation in lung adenocarcinoma.
Athar Khalil;Trang Dinh;Meaghan Parks;Rebecca C,Obeng;Berkley Gryder;Adam Kresak;Yuxiang Wang;Jeff Maltas;Madeline Bedrock;Xiangzhen Wei;Zachary Faber;Mira Rahm;Jacob Scott;Thomas LaFramboise;Zhenghe Wang;Christopher McFarland
Department of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA Cancer Genomics and Epigenomics Program,Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Pathology,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA Department of Pathology,University Hospitals Cleveland Medical Center,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA Cancer Genomics and Epigenomics Program,Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USADepartment of Pathology,University Hospitals Cleveland Medical Center,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA Cancer Genomics and Epigenomics Program,Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USATranslational Hematology & Oncology Research,Cleveland Clinic,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA Cancer Genomics and Epigenomics Program,Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USADepartment of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA Cancer Genomics and Epigenomics Program,Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USA
医药卫生
Early growth response 1In vivo modelsTBX2 subfamilyTuba-seqTumor suppressors
《Genes & Diseases》 2026 (3)
P.507-518,12
supported by grants from the US National Institutes of Health(No.R01CA271540,R00CA226506 to C.M.,R01CA196643,R01CA264320,R01CA260629,P50CA150964,P30 CA043703 to Z.W.).
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