SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
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-n...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2019-02, Vol.79 (4), p.720-734 |
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| creator | Oliphant, Michael U J Vincent, Melanie Y Galbraith, Matthew D Pandey, Ahwan Zaberezhnyy, Vadym Rudra, Pratyaydipta Johnson, Katherine R Costello, James C Ghosh, Debashis DeGregori, James Espinosa, Joaquin M Ford, Heide L |
| description | 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
Srr2 enhancer, promoting
expression and downstream expression of
, which are both key pluripotency factors. Regulation of
by Six2 enhanced cancer stem cell properties and increased metastatic colonization.
and
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.
http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg. |
| doi_str_mv | 10.1158/0008-5472.CAN-18-1791 |
| format | Article |
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Srr2 enhancer, promoting
expression and downstream expression of
, which are both key pluripotency factors. Regulation of
by Six2 enhanced cancer stem cell properties and increased metastatic colonization.
and
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.
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Srr2 enhancer, promoting
expression and downstream expression of
, which are both key pluripotency factors. Regulation of
by Six2 enhanced cancer stem cell properties and increased metastatic colonization.
and
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.
http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Proliferation</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Nanog Homeobox Protein - genetics</subject><subject>Nanog Homeobox Protein - metabolism</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Recurrence, Local - genetics</subject><subject>Neoplasm Recurrence, Local - metabolism</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Prognosis</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Survival Rate</subject><subject>Triple Negative Breast Neoplasms - genetics</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Triple Negative Breast Neoplasms - secondary</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkV9LHDEUxYNYdKt-BEsefRnNzSSZ7Isgo9aFbS1dC30LdzOZbWT-aJIR-u3Noi4thBvuzTknCT9CToGdA0h9wRjThRQVP6-vvhegC6jmsEdmIEtdVELIfTLbaQ7J5xgfcyuByQNyWDLFVMXZjPSrxW9Ov7nGY3KRLnMtVgk3Ls8Sxrx8pC8e6bUPzib6022mDpMfBzq2dHWfzTg0dDE0k_2YIq1xsC7QVXI9rV3X0R9h3ATsj8mnFrvoTt73I_Lr9uahviuW918X9dWysEKVqZAKtW5sk4tbA29bt66k4C2gFgoqQClAYstKpTXYqmRzJnmTxVKuGynm5RG5fMt9mta9a6wbUsDOPAXfY_hrRvTm_5PB_zGb8cUoqRUvRQ44ew8I4_PkYjK9jzb_BAc3TtFwUAIYCM6zVL5JbRhjDK7dXQPMbFGZLQazxWAyKgPabFFl35d_37hzfbApXwH7hY8a</recordid><startdate>20190215</startdate><enddate>20190215</enddate><creator>Oliphant, Michael U J</creator><creator>Vincent, Melanie Y</creator><creator>Galbraith, Matthew D</creator><creator>Pandey, Ahwan</creator><creator>Zaberezhnyy, Vadym</creator><creator>Rudra, Pratyaydipta</creator><creator>Johnson, Katherine R</creator><creator>Costello, James C</creator><creator>Ghosh, Debashis</creator><creator>DeGregori, James</creator><creator>Espinosa, Joaquin M</creator><creator>Ford, Heide L</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3158-9682</orcidid><orcidid>https://orcid.org/0000-0002-1089-7283</orcidid><orcidid>https://orcid.org/0000-0003-0485-3927</orcidid></search><sort><creationdate>20190215</creationdate><title>SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program</title><author>Oliphant, Michael U J ; Vincent, Melanie Y ; Galbraith, Matthew D ; Pandey, Ahwan ; Zaberezhnyy, Vadym ; Rudra, Pratyaydipta ; Johnson, Katherine R ; Costello, James C ; Ghosh, Debashis ; DeGregori, James ; Espinosa, Joaquin M ; Ford, Heide L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-56a88dcd88deb12ffeb7542f1a846171a5415af036881c7309052d8de55bd5493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Proliferation</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Nanog Homeobox Protein - genetics</topic><topic>Nanog Homeobox Protein - metabolism</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Recurrence, Local - genetics</topic><topic>Neoplasm Recurrence, Local - metabolism</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Prognosis</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>SOXB1 Transcription Factors - metabolism</topic><topic>Survival Rate</topic><topic>Triple Negative Breast Neoplasms - genetics</topic><topic>Triple Negative Breast Neoplasms - metabolism</topic><topic>Triple Negative Breast Neoplasms - secondary</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oliphant, Michael U J</creatorcontrib><creatorcontrib>Vincent, Melanie Y</creatorcontrib><creatorcontrib>Galbraith, Matthew D</creatorcontrib><creatorcontrib>Pandey, Ahwan</creatorcontrib><creatorcontrib>Zaberezhnyy, Vadym</creatorcontrib><creatorcontrib>Rudra, Pratyaydipta</creatorcontrib><creatorcontrib>Johnson, Katherine R</creatorcontrib><creatorcontrib>Costello, James C</creatorcontrib><creatorcontrib>Ghosh, Debashis</creatorcontrib><creatorcontrib>DeGregori, James</creatorcontrib><creatorcontrib>Espinosa, Joaquin M</creatorcontrib><creatorcontrib>Ford, Heide L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oliphant, Michael U J</au><au>Vincent, Melanie Y</au><au>Galbraith, Matthew D</au><au>Pandey, Ahwan</au><au>Zaberezhnyy, Vadym</au><au>Rudra, Pratyaydipta</au><au>Johnson, Katherine R</au><au>Costello, James C</au><au>Ghosh, Debashis</au><au>DeGregori, James</au><au>Espinosa, Joaquin M</au><au>Ford, Heide L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2019-02-15</date><risdate>2019</risdate><volume>79</volume><issue>4</issue><spage>720</spage><epage>734</epage><pages>720-734</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>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
Srr2 enhancer, promoting
expression and downstream expression of
, which are both key pluripotency factors. Regulation of
by Six2 enhanced cancer stem cell properties and increased metastatic colonization.
and
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.
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| ispartof | Cancer research (Chicago, Ill.), 2019-02, Vol.79 (4), p.720-734 |
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| language | eng |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cell Proliferation Female Follow-Up Studies Gene Expression Regulation, Neoplastic Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, SCID Nanog Homeobox Protein - genetics Nanog Homeobox Protein - metabolism Neoplasm Metastasis Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - metabolism Neoplasm Recurrence, Local - pathology Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Prognosis SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Survival Rate Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - secondary Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| title | SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program |
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