The Experts below are selected from a list of 81450 Experts worldwide ranked by ideXlab platform
Michael U. J. Oliphant - One of the best experts on this subject based on the ideXlab platform.
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SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
Cancer research, 2019Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Matthew D. Galbraith, James C. Costello, Melanie Y. Vincent, Vadym Zaberezhnyy, Pratyaydipta Rudra, Debashis Ghosh, James DegregoriAbstract:The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the SOX2 Srr2 enhancer, promoting SOX2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of SOX2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and SOX2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.
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Abstract 5001: Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization
Tumor Biology, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
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abstract 5001 identification of a six2 SOX2 nanog stem cell axis that promotes breast cancer metastatic colonization
Cancer Research, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
Heide L Ford - One of the best experts on this subject based on the ideXlab platform.
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Abstract 5001: Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization
Tumor Biology, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
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abstract 5001 identification of a six2 SOX2 nanog stem cell axis that promotes breast cancer metastatic colonization
Cancer Research, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
Matthew D. Galbraith - One of the best experts on this subject based on the ideXlab platform.
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SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
Cancer research, 2019Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Matthew D. Galbraith, James C. Costello, Melanie Y. Vincent, Vadym Zaberezhnyy, Pratyaydipta Rudra, Debashis Ghosh, James DegregoriAbstract:The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the SOX2 Srr2 enhancer, promoting SOX2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of SOX2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and SOX2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.
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Abstract 5001: Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization
Tumor Biology, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
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abstract 5001 identification of a six2 SOX2 nanog stem cell axis that promotes breast cancer metastatic colonization
Cancer Research, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
James C. Costello - One of the best experts on this subject based on the ideXlab platform.
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SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
Cancer research, 2019Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Matthew D. Galbraith, James C. Costello, Melanie Y. Vincent, Vadym Zaberezhnyy, Pratyaydipta Rudra, Debashis Ghosh, James DegregoriAbstract:The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the SOX2 Srr2 enhancer, promoting SOX2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of SOX2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and SOX2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.
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Abstract 5001: Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization
Tumor Biology, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
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abstract 5001 identification of a six2 SOX2 nanog stem cell axis that promotes breast cancer metastatic colonization
Cancer Research, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
Katherine R. Johnson - One of the best experts on this subject based on the ideXlab platform.
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SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
Cancer research, 2019Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Matthew D. Galbraith, James C. Costello, Melanie Y. Vincent, Vadym Zaberezhnyy, Pratyaydipta Rudra, Debashis Ghosh, James DegregoriAbstract:The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the SOX2 Srr2 enhancer, promoting SOX2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of SOX2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and SOX2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.
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Abstract 5001: Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization
Tumor Biology, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
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abstract 5001 identification of a six2 SOX2 nanog stem cell axis that promotes breast cancer metastatic colonization
Cancer Research, 2018Co-Authors: Michael U. J. Oliphant, Ahwan Pandey, Katherine R. Johnson, Rani K. Powers, Matthew D. Galbraith, James C. Costello, Heide L FordAbstract:Although significant progress has been made in understanding the molecular mechanisms that lead to metastatic breast cancer, it remains the overwhelming cause of death for patients. Current studies primarily focus on the prevention of early stages of metastasis, such as migration and invasion. But at the time of diagnosis tumor cells have likely left the primary tumor, suggesting that inhibition of the early stages of metastasis may not be the most effective means of inhibiting metastatic burden. Instead, the identification and targeting of molecules required for establishment and survival of cells at secondary sites is imperative for advancing therapies. We are examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors and is responsible for the maintenance of stem/progenitor cells during nephrogenesis. Using knockdown (KD) and overexpression (OE) models in murine mammary cells, we demonstrated that Six2 promotes specifically late-stage metastasis (growth at the secondary site). RNA-Seq analysis on control and Six2 OE cells showed a dramatic enrichment in stem cell transcriptional programs downstream of Six2 in mammary/breast cancer cells. Flow cytometry analyses and tumorsphere assays demonstrate that Six2 OE leads to an increase, whereas Six2 KD leads to a decrease, in the mammary stem cell population and tumorsphere formation, respectively. Using an immune competent mouse model, in vivo orthotopic limiting-dilution experiments reveal that Six2 regulates tumor initiation. In addition, we show that Six2 regulates late-stage metastasis of human breast cancer cells in vivo, as measured by metastatic burden after tail vein injection. Thus, our data demonstrate that Six2 similarly promotes stem phenotypes in breast cancer cells as it does during kidney development, and suggest that this attribute may be critical for its ability to promote metastatic outgrowth. To determine the molecular mechanism by which Six2 mediates stem phenotypes and metastasis in breast cancer, we interrogated our RNA-seq data, which suggested that Six2 may control master regulators of stemness. We demonstrate that both SOX2 and Nanog are regulated by Six2. In human breast cancer gene expression datasets, Six2 significantly positively correlates with both SOX2 and Nanog, and combined OE of Six2 with either SOX2 or Nanog results in poor prognosis. Preliminary data suggest that loss of SOX2 downstream of Six2 inhibits metastatic outgrowth, and that SOX2 is upstream of Nanog in the pathway. Together, our data demonstrate that Six2 regulates cancer stem phenotypes to promote metastatic outgrowth, uncovering a novel Six2/SOX2/Nanog axis that is critical for metastatic colonization. Citation Format: Michael U. Oliphant, Ahwan Pandey, Katherine Johnson, Rani Powers, Matthew Galbraith, James Costello, Heide L. Ford. Identification of a Six2/SOX2/Nanog stem cell axis that promotes breast cancer metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5001.
