Separation of breast cancer and organ microenvironment transcriptomes in metastases
Abstract Background The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenviro...
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doaj-4c6513371deb4dd18f222731bbba6ee52021-03-02T08:45:08ZengBMCBreast Cancer Research1465-542X2019-03-0121111510.1186/s13058-019-1123-2Separation of breast cancer and organ microenvironment transcriptomes in metastasesMohammad A. Alzubi0Tia H. Turner1Amy L. Olex2Sahib S. Sohal3Nicholas P. Tobin4Susana G. Recio5Jonas Bergh6Thomas Hatschek7Joel S. Parker8Carol A. Sartorius9Charles M. Perou10Mikhail G. Dozmorov11J. Chuck Harrell12Department of Pathology, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth UniversityC. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth UniversityDepartment of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University HospitalDepartment of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillDepartment of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University HospitalDepartment of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University HospitalDepartment of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillDepartment of Pathology, University of Colorado Anschutz Medical CampusDepartment of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillDepartment of Biostatistics, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth UniversityAbstract Background The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression.http://link.springer.com/article/10.1186/s13058-019-1123-2Breast cancerLuciferaseMetastasisMicroenvironmentPatient-derived xenograftRNA sequencing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mohammad A. Alzubi Tia H. Turner Amy L. Olex Sahib S. Sohal Nicholas P. Tobin Susana G. Recio Jonas Bergh Thomas Hatschek Joel S. Parker Carol A. Sartorius Charles M. Perou Mikhail G. Dozmorov J. Chuck Harrell |
spellingShingle |
Mohammad A. Alzubi Tia H. Turner Amy L. Olex Sahib S. Sohal Nicholas P. Tobin Susana G. Recio Jonas Bergh Thomas Hatschek Joel S. Parker Carol A. Sartorius Charles M. Perou Mikhail G. Dozmorov J. Chuck Harrell Separation of breast cancer and organ microenvironment transcriptomes in metastases Breast Cancer Research Breast cancer Luciferase Metastasis Microenvironment Patient-derived xenograft RNA sequencing |
author_facet |
Mohammad A. Alzubi Tia H. Turner Amy L. Olex Sahib S. Sohal Nicholas P. Tobin Susana G. Recio Jonas Bergh Thomas Hatschek Joel S. Parker Carol A. Sartorius Charles M. Perou Mikhail G. Dozmorov J. Chuck Harrell |
author_sort |
Mohammad A. Alzubi |
title |
Separation of breast cancer and organ microenvironment transcriptomes in metastases |
title_short |
Separation of breast cancer and organ microenvironment transcriptomes in metastases |
title_full |
Separation of breast cancer and organ microenvironment transcriptomes in metastases |
title_fullStr |
Separation of breast cancer and organ microenvironment transcriptomes in metastases |
title_full_unstemmed |
Separation of breast cancer and organ microenvironment transcriptomes in metastases |
title_sort |
separation of breast cancer and organ microenvironment transcriptomes in metastases |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2019-03-01 |
description |
Abstract Background The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression. |
topic |
Breast cancer Luciferase Metastasis Microenvironment Patient-derived xenograft RNA sequencing |
url |
http://link.springer.com/article/10.1186/s13058-019-1123-2 |
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