Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

Michael J. Flister; Shirng Wern Tsaih; Alexander Stoddard; Cody Plasterer; Jaidip Jagtap; Abdul K. Parchur; Gayatri Sharma; Anthony R. Prisco; Angela Lemke; Dana Murphy; Mona Al-Gizawiy; Michael Straza; Sophia Ran; Aron M. Geurts; Melinda R. Dwinell; Andrew S. Greene; Carmen Bergom; Peter S. LaViolette; Amit Joshi

doi:10.1007/s10549-017-4311-8

Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

Michael J. Flister, Shirng Wern Tsaih, Alexander Stoddard, Cody Plasterer, Jaidip Jagtap, Abdul K. Parchur, Gayatri Sharma, Anthony R. Prisco, Angela Lemke, Dana Murphy, Mona Al-Gizawiy, Michael Straza, Sophia Ran, Aron M. Geurts, Melinda R. Dwinell, Andrew S. Greene, Carmen Bergom, Peter S. LaViolette, Amit Joshi

Medicine - Administration

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 SS^IL2Rγ and SS.BN3^IL2Rγ CXM strains. Results: Breast cancer xenografts implanted in SS.BN3^IL2Rγ (consomic) had significant tumor growth inhibition compared with SS^IL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3^IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3^IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SS^IL2Rγ and SS.BN3^IL2Rγ 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.BN3^IL2Rγ tumors compared with SS^IL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3^IL2Rγ 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.

Original language	English (US)
Pages (from-to)	53-64
Number of pages	12
Journal	Breast Cancer Research and Treatment
Volume	165
Issue number	1
DOIs	https://doi.org/10.1007/s10549-017-4311-8
State	Published - Aug 1 2017

Bibliographical note

Funding Information:
We thank M. Tschannen, R. Schilling, E. Schneider, A. Zappa, and Y. Liu for excellent technical support and the Center for Imaging Research in the Medical College of Wisconsin Department of Radiology, and the Biomedical Imaging Shared Resource supported by the MCW Cancer Center.

Funding Information:
This work was supported by a seed grant from the Wisconsin Breast Cancer Showhouse and the MCW Cancer Center, the Mary Kay Foundation (Grant No. 024.16), and the NCI (R01CA193343) to M.J.F. Support was also received from the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the Office of the Director of the NIH via the Clinical & Translational Science Institute (#8KL2TR000056), the Wisconsin Breast Cancer Showhouse and the MCW Cancer Center, the Rosenberg Translational Research Award, and an institutional research Grant (#86-004-26) from the American Cancer Society to C.B.

Publisher Copyright:
© 2017, Springer Science+Business Media New York.

Keywords

Breast cancer
Genomics
Imaging
RNA sequencing
Tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1007/s10549-017-4311-8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404538

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Flister, M. J., Tsaih, S. W., Stoddard, A., Plasterer, C., Jagtap, J., Parchur, A. K., Sharma, G., Prisco, A. R., Lemke, A., Murphy, D., Al-Gizawiy, M., Straza, M., Ran, S., Geurts, A. M., Dwinell, M. R., Greene, A. S., Bergom, C., LaViolette, P. S., & Joshi, A. (2017). Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. Breast Cancer Research and Treatment, 165(1), 53-64. https://doi.org/10.1007/s10549-017-4311-8

Flister, MJ, Tsaih, SW, Stoddard, A, Plasterer, C, Jagtap, J, Parchur, AK, Sharma, G, Prisco, AR, Lemke, A, Murphy, D, Al-Gizawiy, M, Straza, M, Ran, S, Geurts, AM, Dwinell, MR, Greene, AS, Bergom, C, LaViolette, PS & Joshi, A 2017, 'Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer', Breast Cancer Research and Treatment, vol. 165, no. 1, pp. 53-64. https://doi.org/10.1007/s10549-017-4311-8

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title = "Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer",

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.",

keywords = "Breast cancer, Genomics, Imaging, RNA sequencing, Tumor microenvironment",

author = "Flister, {Michael J.} and Tsaih, {Shirng Wern} and Alexander Stoddard and Cody Plasterer and Jaidip Jagtap and Parchur, {Abdul K.} and Gayatri Sharma and Prisco, {Anthony R.} and Angela Lemke and Dana Murphy and Mona Al-Gizawiy and Michael Straza and Sophia Ran and Geurts, {Aron M.} and Dwinell, {Melinda R.} and Greene, {Andrew S.} and Carmen Bergom and LaViolette, {Peter S.} and Amit Joshi",

note = "Funding Information: We thank M. Tschannen, R. Schilling, E. Schneider, A. Zappa, and Y. Liu for excellent technical support and the Center for Imaging Research in the Medical College of Wisconsin Department of Radiology, and the Biomedical Imaging Shared Resource supported by the MCW Cancer Center. Funding Information: This work was supported by a seed grant from the Wisconsin Breast Cancer Showhouse and the MCW Cancer Center, the Mary Kay Foundation (Grant No. 024.16), and the NCI (R01CA193343) to M.J.F. Support was also received from the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the Office of the Director of the NIH via the Clinical & Translational Science Institute (#8KL2TR000056), the Wisconsin Breast Cancer Showhouse and the MCW Cancer Center, the Rosenberg Translational Research Award, and an institutional research Grant (#86-004-26) from the American Cancer Society to C.B. Publisher Copyright: {\textcopyright} 2017, Springer Science+Business Media New York.",

year = "2017",

month = aug,

day = "1",

doi = "10.1007/s10549-017-4311-8",

language = "English (US)",

volume = "165",

pages = "53--64",

journal = "Breast Cancer Research and Treatment",

issn = "0167-6806",

publisher = "Springer",

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TY - JOUR

T1 - Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

AU - Flister, Michael J.

AU - Tsaih, Shirng Wern

AU - Stoddard, Alexander

AU - Plasterer, Cody

AU - Jagtap, Jaidip

AU - Parchur, Abdul K.

AU - Sharma, Gayatri

AU - Prisco, Anthony R.

AU - Lemke, Angela

AU - Murphy, Dana

AU - Al-Gizawiy, Mona

AU - Straza, Michael

AU - Ran, Sophia

AU - Geurts, Aron M.

AU - Dwinell, Melinda R.

AU - Greene, Andrew S.

AU - Bergom, Carmen

AU - LaViolette, Peter S.

AU - Joshi, Amit

N1 - Funding Information: We thank M. Tschannen, R. Schilling, E. Schneider, A. Zappa, and Y. Liu for excellent technical support and the Center for Imaging Research in the Medical College of Wisconsin Department of Radiology, and the Biomedical Imaging Shared Resource supported by the MCW Cancer Center. Funding Information: This work was supported by a seed grant from the Wisconsin Breast Cancer Showhouse and the MCW Cancer Center, the Mary Kay Foundation (Grant No. 024.16), and the NCI (R01CA193343) to M.J.F. Support was also received from the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the Office of the Director of the NIH via the Clinical & Translational Science Institute (#8KL2TR000056), the Wisconsin Breast Cancer Showhouse and the MCW Cancer Center, the Rosenberg Translational Research Award, and an institutional research Grant (#86-004-26) from the American Cancer Society to C.B. Publisher Copyright: © 2017, Springer Science+Business Media New York.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Genomics

KW - Imaging

KW - RNA sequencing

KW - Tumor microenvironment

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SN - 0167-6806

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JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

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Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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