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Primary tumor grafts as advanced models for breast cancer that authentically reflect tumor histopathology, growth, metastasis, and patient outcomes (copy number)

ABSTRACT: Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32530 | GEO | 2011/10/23

SECONDARY ACCESSION(S): PRJNA154437

REPOSITORIES: GEO

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Primary tumor grafts as advanced models for breast cancer that authentically reflect tumor histopathology, growth, metastasis, and patient outcomes (copy number)

Project description:Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer. Single replicates of genomic DNA from 12 human breast cancer tumors and xenografts of those tumors in immunodeficient mice were hybridized to Affymetrix Human SNP 6.0 genotyping arrays.

2011-10-22 | E-GEOD-32530 | biostudies-arrayexpress

Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes (expression)

Project description:Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce tumor growth and metastatic progression. We report new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These tumor grafts represent the diversity of human breast cancer and maintain essential features of the original tumors, including metastasis to specific sites. Co-engraftment of primary human mesenchymal stem cells maintains phenotypic stability of the grafts and increases tumor growth by promoting angiogenesis. We also report that tumor engraftment is a prognostic indicator of disease outcome for newly diagnosed women; orthotopic breast tumor grafting marks a step toward individualized models for tumor growth, metastasis, and prognosis. This bank of tumor grafts also serves as a publicly available resource for new models in which to study the biology of breast cancer. Single replicates of total RNA from 12 human breast cancer tumors and xenografts of those tumors in immunodeficient mice were hybridized to Agilent Whole Human Genome expression arrays.

2011-10-22 | E-GEOD-32531 | biostudies-arrayexpress

Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes (expression)

2011-10-23 | GSE32531 | GEO

Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes

Project description:This SuperSeries is composed of the following subset Series: GSE32530: Primary tumorgrafts as advanced models for breast cancer that authentically reflect tumor histopathology, growth, metastasis, and patient outcomes (copy number) GSE32531: Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes (expression) Refer to individual Series

2011-10-22 | E-GEOD-32532 | biostudies-arrayexpress

Homo sapiens

Project description:Primary tumor grafts as advanced models for breast cancer that authentically reflect tumor histopathology, growth, metastasis, and patient outcomes (copy number)

| PRJNA154437 | ENA

Project description:Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes

| PRJNA147817 | ENA

Homo sapiens

Project description:Patient-derived tumor grafts authentically reflect tumor pathology, growth, metastasis, and disease outcomes (expression)

| PRJNA154439 | ENA

The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (gene expression array)

Project description:Metastasis is the major cause of death in cancer patients, yet the genetic/epigenetic programs that drive metastasis are poorly understood. Here, we report a novel epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci, and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a new pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo. To determine the molecular mechanisms by which RON/MSP drives breast cancer metastasis, we performed microarray gene expression profiling of MCF7, MCF7-RON/MSP and MCF7-RON/MSP-shMBD4 cells.

2014-01-02 | E-GEOD-52567 | biostudies-arrayexpress

The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (RNA-Seq)

Project description:Metastasis is the major cause of death in cancer patients, yet the genetic/epigenetic programs that drive metastasis are poorly understood. Here, we report a novel epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci, and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers using a set of specific genes that are regulated by RON/MSP through MBD4-directed aberrant DNA methylation revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a new pharmacological agent prevents activation of the RON/MBD4 pathway and blocks metastasis of patient-derived breast tumor grafts in vivo. Examination of 3 cell types.

2014-01-02 | E-GEOD-52687 | biostudies-arrayexpress

ATM-inhibitor AZD1390 is a radiosensitizer for breast cancer CNS metastasis

Project description:Purpose: Central nervous system (CNS) metastasis has remained a major source of mortality for breast cancer patients. This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated (ATM) inhibitor, as a radiosensitizer for breast cancer CNS metastasis treatment. Experimental Design: Three PDX tumors including 2 HER2+ and 1 triple negative breast cancer (TNBC) harboring TP53 mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. Results: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival 222 days compared to 123 days in controls. Adjuvant administration of AZD1390 had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in in some mice 50-100 days post-treatment in all models. Gene expression analysis comparing these tumors with complete responders demonstrated changes in upregulation of multiple oncogenic proteins, which are potential drivers of tumor growth after treatment. Conclusions: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CNS metastasis to radiation therapy in TP53 mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CNS metastasis.

2023-08-01 | GSE224899 | GEO

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