A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures
Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic micr...
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| Veröffentlicht in: | Molecular & cellular proteomics 2018-04, Vol.17 (4), p.619-630 |
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| creator | Clark, Amanda M. Kumar, Manu P. Wheeler, Sarah E. Young, Carissa L. Venkataramanan, Raman Stolz, Donna B. Griffith, Linda G. Lauffenburger, Douglas A. Wells, Alan |
| description | Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS with small numbers ( |
| doi_str_mv | 10.1074/mcp.RA117.000370 |
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In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS with small numbers (<0.05% by cell count) of the aggressive MDA-MB-231 breast cancer cell line, two populations formed: actively proliferating (“growing”; EdU+), and spontaneously quiescent (“dormant”; EdU−). Following treatment with a clinically standard chemotherapeutic, the proliferating cells were eliminated and only quiescent cells remained; this residual dormant population could then be induced to a proliferative state (“emergent”; EdU+) by physiologically-relevant inflammatory stimuli, lipopolysaccharide (LPS) and epidermal growth factor (EGF). Multiplexed proteomic analysis of the MPS effluent enabled elucidation of key factors and processes that correlated with the various tumor cell states, and candidate biomarkers for actively proliferating (either primary or secondary emergence) versus dormant metastatic cells in liver tissue. Dormancy was found to be associated with signaling reflective of cellular quiescence even more strongly than the original tumor-free liver tissue, whereas proliferative nodules presented inflammatory signatures. Given the minimal tumor burden, these markers likely represent changes in the tumor microenvironment rather than in the tumor cells. A computational decision tree algorithm applied to these signatures indicated the potential of this MPS for clinical discernment of each metastatic stage from blood protein analysis.</description><identifier>ISSN: 1535-9476</identifier><identifier>ISSN: 1535-9484</identifier><identifier>EISSN: 1535-9484</identifier><identifier>DOI: 10.1074/mcp.RA117.000370</identifier><identifier>PMID: 29353230</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Biomarkers ; Biomarkers, Tumor - metabolism ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cell Line, Tumor ; Computer applications ; Dormancy ; Emergence ; Epidermal growth factor ; Female ; Hepatocytes ; Humans ; Inflammation ; Lipopolysaccharides ; Liver ; Liver - metabolism ; Liver - pathology ; Male ; Metastases ; Metastasis ; Nodules ; Signaling ; Tumor cells ; Tumors</subject><ispartof>Molecular & cellular proteomics, 2018-04, Vol.17 (4), p.619-630</ispartof><rights>2018 © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>2018 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>Copyright American Society for Biochemistry and Molecular Biology Apr 2018</rights><rights>2018 by The American Society for Biochemistry and Molecular Biology, Inc. 2018 The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-421d1565d5c018369d366f3072e01558b87c4c32a365fbc08420f73fddf8f1eb3</citedby><cites>FETCH-LOGICAL-c475t-421d1565d5c018369d366f3072e01558b87c4c32a365fbc08420f73fddf8f1eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880110/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880110/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29353230$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Clark, Amanda M.</creatorcontrib><creatorcontrib>Kumar, Manu P.</creatorcontrib><creatorcontrib>Wheeler, Sarah E.</creatorcontrib><creatorcontrib>Young, Carissa L.</creatorcontrib><creatorcontrib>Venkataramanan, Raman</creatorcontrib><creatorcontrib>Stolz, Donna B.</creatorcontrib><creatorcontrib>Griffith, Linda G.</creatorcontrib><creatorcontrib>Lauffenburger, Douglas A.</creatorcontrib><creatorcontrib>Wells, Alan</creatorcontrib><title>A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures</title><title>Molecular & cellular proteomics</title><addtitle>Mol Cell Proteomics</addtitle><description>Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS with small numbers (<0.05% by cell count) of the aggressive MDA-MB-231 breast cancer cell line, two populations formed: actively proliferating (“growing”; EdU+), and spontaneously quiescent (“dormant”; EdU−). Following treatment with a clinically standard chemotherapeutic, the proliferating cells were eliminated and only quiescent cells remained; this residual dormant population could then be induced to a proliferative state (“emergent”; EdU+) by physiologically-relevant inflammatory stimuli, lipopolysaccharide (LPS) and epidermal growth factor (EGF). Multiplexed proteomic analysis of the MPS effluent enabled elucidation of key factors and processes that correlated with the various tumor cell states, and candidate biomarkers for actively proliferating (either primary or secondary emergence) versus dormant metastatic cells in liver tissue. Dormancy was found to be associated with signaling reflective of cellular quiescence even more strongly than the original tumor-free liver tissue, whereas proliferative nodules presented inflammatory signatures. Given the minimal tumor burden, these markers likely represent changes in the tumor microenvironment rather than in the tumor cells. A computational decision tree algorithm applied to these signatures indicated the potential of this MPS for clinical discernment of each metastatic stage from blood protein analysis.</description><subject>Biomarkers</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Computer applications</subject><subject>Dormancy</subject><subject>Emergence</subject><subject>Epidermal growth factor</subject><subject>Female</subject><subject>Hepatocytes</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Lipopolysaccharides</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Nodules</subject><subject>Signaling</subject><subject>Tumor cells</subject><subject>Tumors</subject><issn>1535-9476</issn><issn>1535-9484</issn><issn>1535-9484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1v1DAQxSMEoh9w54QiceGSZWzHccwBabtdoFIrEB9ny7EnwSWxFzup4L_HsGVVkDh55PnN07x5RfGEwIqAqF9MZrf6sCZErACACbhXHBPOeCXrtr5_qEVzVJykdA1AgQj-sDiiknFGGRwX07q8ChbHMvTleYiT9nO1nTAO6OfyCmedZj07U55FzGW50d5gLN_HMERMyQVfbr3uRueHcvt9N4aY6fyZ1c5cmHT8mumPbvB6XvLAo-JBr8eEj2_f0-Lz6-2nzdvq8t2bi836sjK14HNVU2IJb7jlBkjLGmlZ0_QMBEUgnLddK0xtGNWs4X1noK0p9IL11vZtT7Bjp8Wrve5u6Sa0JpuJelS76PJKP1TQTv3d8e6LGsKN4m0LhEAWeH4rEMO3BdOsJpcMjqP2GJakiGylJESKJqPP_kGvwxJ9tqdoPjiVtaQ0U7CnTAwpRewPyxBQv7JUOUv1O0u1zzKPPL1r4jDwJ7wMvNwDmE954zCqZBzmgKyLaGZlg_u_-k8SZq8M</recordid><startdate>20180401</startdate><enddate>20180401</enddate><creator>Clark, Amanda M.</creator><creator>Kumar, Manu P.</creator><creator>Wheeler, Sarah E.</creator><creator>Young, Carissa L.</creator><creator>Venkataramanan, Raman</creator><creator>Stolz, Donna B.</creator><creator>Griffith, Linda G.</creator><creator>Lauffenburger, Douglas A.</creator><creator>Wells, Alan</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><general>The American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180401</creationdate><title>A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures</title><author>Clark, Amanda M. ; Kumar, Manu P. ; Wheeler, Sarah E. ; Young, Carissa L. ; Venkataramanan, Raman ; Stolz, Donna B. ; Griffith, Linda G. ; Lauffenburger, Douglas A. ; Wells, Alan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-421d1565d5c018369d366f3072e01558b87c4c32a365fbc08420f73fddf8f1eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Biomarkers</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Computer applications</topic><topic>Dormancy</topic><topic>Emergence</topic><topic>Epidermal growth factor</topic><topic>Female</topic><topic>Hepatocytes</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Lipopolysaccharides</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Male</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Nodules</topic><topic>Signaling</topic><topic>Tumor cells</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clark, Amanda M.</creatorcontrib><creatorcontrib>Kumar, Manu P.</creatorcontrib><creatorcontrib>Wheeler, Sarah E.</creatorcontrib><creatorcontrib>Young, Carissa L.</creatorcontrib><creatorcontrib>Venkataramanan, Raman</creatorcontrib><creatorcontrib>Stolz, Donna B.</creatorcontrib><creatorcontrib>Griffith, Linda G.</creatorcontrib><creatorcontrib>Lauffenburger, Douglas A.</creatorcontrib><creatorcontrib>Wells, Alan</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular & cellular proteomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clark, Amanda M.</au><au>Kumar, Manu P.</au><au>Wheeler, Sarah E.</au><au>Young, Carissa L.</au><au>Venkataramanan, Raman</au><au>Stolz, Donna B.</au><au>Griffith, Linda G.</au><au>Lauffenburger, Douglas A.</au><au>Wells, Alan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures</atitle><jtitle>Molecular & cellular proteomics</jtitle><addtitle>Mol Cell Proteomics</addtitle><date>2018-04-01</date><risdate>2018</risdate><volume>17</volume><issue>4</issue><spage>619</spage><epage>630</epage><pages>619-630</pages><issn>1535-9476</issn><issn>1535-9484</issn><eissn>1535-9484</eissn><abstract>Breast cancer mortality predominantly results from dormant micrometastases that emerge as fatal outgrowths years after initial diagnosis. In order to gain insights concerning factors associated with emergence of liver metastases, we recreated spontaneous dormancy in an all-human ex vivo hepatic microphysiological system (MPS). Seeding this MPS with small numbers (<0.05% by cell count) of the aggressive MDA-MB-231 breast cancer cell line, two populations formed: actively proliferating (“growing”; EdU+), and spontaneously quiescent (“dormant”; EdU−). Following treatment with a clinically standard chemotherapeutic, the proliferating cells were eliminated and only quiescent cells remained; this residual dormant population could then be induced to a proliferative state (“emergent”; EdU+) by physiologically-relevant inflammatory stimuli, lipopolysaccharide (LPS) and epidermal growth factor (EGF). Multiplexed proteomic analysis of the MPS effluent enabled elucidation of key factors and processes that correlated with the various tumor cell states, and candidate biomarkers for actively proliferating (either primary or secondary emergence) versus dormant metastatic cells in liver tissue. Dormancy was found to be associated with signaling reflective of cellular quiescence even more strongly than the original tumor-free liver tissue, whereas proliferative nodules presented inflammatory signatures. Given the minimal tumor burden, these markers likely represent changes in the tumor microenvironment rather than in the tumor cells. A computational decision tree algorithm applied to these signatures indicated the potential of this MPS for clinical discernment of each metastatic stage from blood protein analysis.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29353230</pmid><doi>10.1074/mcp.RA117.000370</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Biomarkers Biomarkers, Tumor - metabolism Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cell Line, Tumor Computer applications Dormancy Emergence Epidermal growth factor Female Hepatocytes Humans Inflammation Lipopolysaccharides Liver Liver - metabolism Liver - pathology Male Metastases Metastasis Nodules Signaling Tumor cells Tumors |
| title | A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures |
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