Michael J Flister1,2,3, Shirng-Wern Tsaih4,5,6, Alexander Stoddard4, Cody Plasterer4,5,6, Jaidip Jagtap5,7, Abdul K Parchur5,7, Gayatri Sharma5,7, Anthony R Prisco6, Angela Lemke4,5,6, Dana Murphy4,5,6, Mona Al-Gizawiy5,7, Michael Straza5,8, Sophia Ran9,10, Aron M Geurts4,6, Melinda R Dwinell4,5,6, Andrew S Greene6, Carmen Bergom5,8, Peter S LaViolette5,7, Amit Joshi5,7. 1. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA. mflister@mcw.edu. 2. Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. mflister@mcw.edu. 3. Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA. mflister@mcw.edu. 4. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA. 5. Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. 6. Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA. 7. Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA. 8. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. 9. Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, USA. 10. Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Abstract
PURPOSE: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function. METHODS: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SSIL2Rγ and SS.BN3IL2Rγ CXM strains. RESULTS: Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant tumor growth inhibition compared with SSIL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rγ and SS.BN3IL2Rγ tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells, all of which revealed altered vascular function in SS.BN3IL2Rγ tumors compared with SSIL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rγ tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95-131 Mb) that was identified by congenic mapping. CONCLUSIONS: Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.
PURPOSE: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function. METHODS: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, humanbreast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SSIL2Rγ and SS.BN3IL2Rγ CXM strains. RESULTS:Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant tumor growth inhibition compared with SSIL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rγ and SS.BN3IL2Rγ tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells, all of which revealed altered vascular function in SS.BN3IL2Rγ tumors compared with SSIL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rγ tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95-131 Mb) that was identified by congenic mapping. CONCLUSIONS: Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.
Entities:
Keywords:
Breast cancer; Genomics; Imaging; RNA sequencing; Tumor microenvironment
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