A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer
Summary: Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogen...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471731447X |
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doaj-32915cd9ec2440a18a2d27b0b6c96083 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Paul Savage Alexis Blanchet-Cohen Timothée Revil Dunarel Badescu Sadiq M.I. Saleh Yu-Chang Wang Dongmei Zuo Leah Liu Nicholas R. Bertos Valentina Munoz-Ramos Mark Basik Kevin Petrecca Jamil Asselah Sarkis Meterissian Marie-Christine Guiot Atilla Omeroglu Claudia L. Kleinman Morag Park Jiannis Ragoussis |
| spellingShingle |
Paul Savage Alexis Blanchet-Cohen Timothée Revil Dunarel Badescu Sadiq M.I. Saleh Yu-Chang Wang Dongmei Zuo Leah Liu Nicholas R. Bertos Valentina Munoz-Ramos Mark Basik Kevin Petrecca Jamil Asselah Sarkis Meterissian Marie-Christine Guiot Atilla Omeroglu Claudia L. Kleinman Morag Park Jiannis Ragoussis A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer Cell Reports |
| author_facet |
Paul Savage Alexis Blanchet-Cohen Timothée Revil Dunarel Badescu Sadiq M.I. Saleh Yu-Chang Wang Dongmei Zuo Leah Liu Nicholas R. Bertos Valentina Munoz-Ramos Mark Basik Kevin Petrecca Jamil Asselah Sarkis Meterissian Marie-Christine Guiot Atilla Omeroglu Claudia L. Kleinman Morag Park Jiannis Ragoussis |
| author_sort |
Paul Savage |
| title |
A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer |
| title_short |
A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer |
| title_full |
A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer |
| title_fullStr |
A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer |
| title_full_unstemmed |
A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer |
| title_sort |
targetable egfr-dependent tumor-initiating program in breast cancer |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2017-10-01 |
| description |
Summary: Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention. : Savage et al. demonstrate that sensitivity to EGFR inhibitor, gefitinib, in triple-negative breast cancer is paradoxically associated with EGFR heterogeneity. Using single-cell RNA sequencing in conjunction with functional assays, they identify TNBC tumors in which EGFR expression identifies cells with tumor-initiating capacity whose proliferative expansion is sensitive to EGFR inhibition. Keywords: breast cancer, tumor heterogeneity, patient-derived xenograft, single-cell RNA sequencing, EGFR inhibition, therapeutic response, tumor-initiating cell, cell hierarchy, BRCA1 mutation |
| url |
http://www.sciencedirect.com/science/article/pii/S221112471731447X |
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doaj-32915cd9ec2440a18a2d27b0b6c960832020-11-24T20:52:15ZengElsevierCell Reports2211-12472017-10-0121511401149A Targetable EGFR-Dependent Tumor-Initiating Program in Breast CancerPaul Savage0Alexis Blanchet-Cohen1Timothée Revil2Dunarel Badescu3Sadiq M.I. Saleh4Yu-Chang Wang5Dongmei Zuo6Leah Liu7Nicholas R. Bertos8Valentina Munoz-Ramos9Mark Basik10Kevin Petrecca11Jamil Asselah12Sarkis Meterissian13Marie-Christine Guiot14Atilla Omeroglu15Claudia L. Kleinman16Morag Park17Jiannis Ragoussis18Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, Canada; Department of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, CanadaLady Davis Research Institute, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, CanadaDepartment of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1A4, CanadaDepartment of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1A4, CanadaRosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, CanadaDepartment of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1A4, CanadaRosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, CanadaRosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, CanadaRosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, CanadaRosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, CanadaLady Davis Research Institute, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montréal, QC H4A 3T2, Canada; Department of Surgery, McGill University, Montréal, QC H3G 1A4, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, CanadaDepartment of Oncology, McGill University, Montréal, QC H4A 3T2, CanadaDepartment of Oncology, McGill University, Montréal, QC H4A 3T2, Canada; Department of Surgery, McGill University, Montréal, QC H3G 1A4, CanadaDepartment of Pathology, McGill University, Montréal, QC H3A 2B4, CanadaDepartment of Pathology, McGill University, Montréal, QC H3A 2B4, CanadaLady Davis Research Institute, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; Jewish General Hospital, Montréal, QC H3T 1E2, CanadaRosalind & Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3G 0B1, Canada; Department of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Department of Oncology, McGill University, Montréal, QC H4A 3T2, Canada; Department of Pathology, McGill University, Montréal, QC H3A 2B4, Canada; Corresponding authorDepartment of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1A4, Canada; Center of Innovation in Personalized Medicine, Cancer and Mutagen Unit, King Fahd Center for Medical Research, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia; Corresponding authorSummary: Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention. : Savage et al. demonstrate that sensitivity to EGFR inhibitor, gefitinib, in triple-negative breast cancer is paradoxically associated with EGFR heterogeneity. Using single-cell RNA sequencing in conjunction with functional assays, they identify TNBC tumors in which EGFR expression identifies cells with tumor-initiating capacity whose proliferative expansion is sensitive to EGFR inhibition. Keywords: breast cancer, tumor heterogeneity, patient-derived xenograft, single-cell RNA sequencing, EGFR inhibition, therapeutic response, tumor-initiating cell, cell hierarchy, BRCA1 mutationhttp://www.sciencedirect.com/science/article/pii/S221112471731447X |