A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma
A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit. Lung cancer niche drives tumour growth Lung adenoc...
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| Veröffentlicht in: | Nature (London) 2017-05, Vol.545 (7654), p.355-359 |
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| creator | Tammela, Tuomas Sanchez-Rivera, Francisco J. Cetinbas, Naniye Malli Wu, Katherine Joshi, Nikhil S. Helenius, Katja Park, Yoona Azimi, Roxana Kerper, Natanya R. Wesselhoeft, R. Alexander Gu, Xin Schmidt, Leah Cornwall-Brady, Milton Yilmaz, Ömer H. Xue, Wen Katajisto, Pekka Bhutkar, Arjun Jacks, Tyler |
| description | A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit.
Lung cancer niche drives tumour growth
Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome. Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells. One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands. The latter population fuels tumour growth of the former, showing that lung cancer cells can produce their own niche. These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications.
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells
1
,
2
. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration
3
,
4
,
5
. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies. |
| doi_str_mv | 10.1038/nature22334 |
| format | Article |
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Lung cancer niche drives tumour growth
Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome. Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells. One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands. The latter population fuels tumour growth of the former, showing that lung cancer cells can produce their own niche. These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications.
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells
1
,
2
. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration
3
,
4
,
5
. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature22334</identifier><identifier>PMID: 28489818</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/106 ; 13/31 ; 13/89 ; 38 ; 38/109 ; 38/77 ; 42 ; 42/44 ; 631/67/1059/602 ; 631/67/1612/1350 ; 631/67/2329 ; 631/67/71 ; Adenocarcinoma ; Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Adenocarcinoma of Lung ; Animals ; Anticancer properties ; Cancer cells ; Cancer metastasis ; Cancer research ; Cell Proliferation - drug effects ; Disease Progression ; Drug resistance ; Female ; Gene expression ; Growth factors ; Heterogeneity ; Histology ; Humanities and Social Sciences ; Humans ; letter ; Ligands ; Lung cancer ; Lung diseases ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Male ; Medical research ; Mice ; multidisciplinary ; Neoplasm Transplantation ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Perturbation ; Phenotypes ; Protein Processing, Post-Translational - drug effects ; Science ; Signal transduction ; Signaling ; Small Molecule Libraries - pharmacology ; Stem Cell Niche ; Stem cell transplantation ; Stem cells ; Subpopulations ; Survival Rate ; Tumors ; Wnt protein ; Wnt Proteins - biosynthesis ; Wnt Proteins - chemistry ; Wnt Proteins - metabolism ; Wnt Signaling Pathway</subject><ispartof>Nature (London), 2017-05, Vol.545 (7654), p.355-359</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 18, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c752t-eb1142e774a96eba6116084dc34c1da408f1dfd72c9d35fc84dd0404fa24b9413</citedby><cites>FETCH-LOGICAL-c752t-eb1142e774a96eba6116084dc34c1da408f1dfd72c9d35fc84dd0404fa24b9413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature22334$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature22334$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,550,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28489818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:135857975$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Tammela, Tuomas</creatorcontrib><creatorcontrib>Sanchez-Rivera, Francisco J.</creatorcontrib><creatorcontrib>Cetinbas, Naniye Malli</creatorcontrib><creatorcontrib>Wu, Katherine</creatorcontrib><creatorcontrib>Joshi, Nikhil S.</creatorcontrib><creatorcontrib>Helenius, Katja</creatorcontrib><creatorcontrib>Park, Yoona</creatorcontrib><creatorcontrib>Azimi, Roxana</creatorcontrib><creatorcontrib>Kerper, Natanya R.</creatorcontrib><creatorcontrib>Wesselhoeft, R. Alexander</creatorcontrib><creatorcontrib>Gu, Xin</creatorcontrib><creatorcontrib>Schmidt, Leah</creatorcontrib><creatorcontrib>Cornwall-Brady, Milton</creatorcontrib><creatorcontrib>Yilmaz, Ömer H.</creatorcontrib><creatorcontrib>Xue, Wen</creatorcontrib><creatorcontrib>Katajisto, Pekka</creatorcontrib><creatorcontrib>Bhutkar, Arjun</creatorcontrib><creatorcontrib>Jacks, Tyler</creatorcontrib><title>A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit.
Lung cancer niche drives tumour growth
Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome. Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells. One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands. The latter population fuels tumour growth of the former, showing that lung cancer cells can produce their own niche. These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications.
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells
1
,
2
. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration
3
,
4
,
5
. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.</description><subject>13</subject><subject>13/106</subject><subject>13/31</subject><subject>13/89</subject><subject>38</subject><subject>38/109</subject><subject>38/77</subject><subject>42</subject><subject>42/44</subject><subject>631/67/1059/602</subject><subject>631/67/1612/1350</subject><subject>631/67/2329</subject><subject>631/67/71</subject><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma of Lung</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Cancer cells</subject><subject>Cancer metastasis</subject><subject>Cancer research</subject><subject>Cell Proliferation - drug effects</subject><subject>Disease Progression</subject><subject>Drug resistance</subject><subject>Female</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Heterogeneity</subject><subject>Histology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>letter</subject><subject>Ligands</subject><subject>Lung cancer</subject><subject>Lung diseases</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Male</subject><subject>Medical research</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Neoplasm Transplantation</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Perturbation</subject><subject>Phenotypes</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Science</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Stem Cell Niche</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Subpopulations</subject><subject>Survival Rate</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Wnt Proteins - biosynthesis</subject><subject>Wnt Proteins - chemistry</subject><subject>Wnt Proteins - metabolism</subject><subject>Wnt Signaling Pathway</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><sourceid>D8T</sourceid><recordid>eNp1kk1v1DAQhi0EokvhxB1F9AKCFDtxHPuCtFrxUakCCYp64GB57UnqktipnRT493jVpd2gRT7YnveZ1xrPIPSU4GOCS_7GqXEKUBRlSe-hBaE1yynj9X20wLjgOeYlO0CPYrzEGFekpg_RQcEpF5zwBfq-zM7dmA_Bm0lb12bO6gvITLDXELMU7mwDQY3pmg1-BDda1WXKmY3WBojRepdZl3VTSlYGnNcqJCffq8foQaO6CE-2-yH69v7d2epjfvr5w8lqeZrruirGHNaE0ALqmirBYK0YIQxzanRJNTGKYt4Q05i60MKUVaOTZDDFtFEFXQtKykOU3_jGnzBMazkE26vwW3pl5Tb0I51AUsEEpol_e8MnpQejU1FBdbO0ueLshWz9tawELlnNk8GLrUHwVxPEUfY2aug65cBPURIuao6rohIJPfoHvfRTcOk7JBGYEM5pVd1RrepAWtf49K7emMplhSkVghF2V-eMasGlBnXeQWNTeMY_38PrwV7JXeh4D5SWgd7qva4vZwmJGeHX2KopRnny9cucffV_dnl2vvq0l9bBxxiguW0JwXIz6nJn1BP9bLeLt-zf2U7A6-1YJMm1EHa-fo_fH_rfB2Y</recordid><startdate>20170518</startdate><enddate>20170518</enddate><creator>Tammela, Tuomas</creator><creator>Sanchez-Rivera, Francisco J.</creator><creator>Cetinbas, Naniye Malli</creator><creator>Wu, Katherine</creator><creator>Joshi, Nikhil S.</creator><creator>Helenius, Katja</creator><creator>Park, Yoona</creator><creator>Azimi, Roxana</creator><creator>Kerper, Natanya R.</creator><creator>Wesselhoeft, R. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tammela, Tuomas</au><au>Sanchez-Rivera, Francisco J.</au><au>Cetinbas, Naniye Malli</au><au>Wu, Katherine</au><au>Joshi, Nikhil S.</au><au>Helenius, Katja</au><au>Park, Yoona</au><au>Azimi, Roxana</au><au>Kerper, Natanya R.</au><au>Wesselhoeft, R. Alexander</au><au>Gu, Xin</au><au>Schmidt, Leah</au><au>Cornwall-Brady, Milton</au><au>Yilmaz, Ömer H.</au><au>Xue, Wen</au><au>Katajisto, Pekka</au><au>Bhutkar, Arjun</au><au>Jacks, Tyler</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2017-05-18</date><risdate>2017</risdate><volume>545</volume><issue>7654</issue><spage>355</spage><epage>359</epage><pages>355-359</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit.
Lung cancer niche drives tumour growth
Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome. Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells. One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands. The latter population fuels tumour growth of the former, showing that lung cancer cells can produce their own niche. These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications.
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells
1
,
2
. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration
3
,
4
,
5
. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28489818</pmid><doi>10.1038/nature22334</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2017-05, Vol.545 (7654), p.355-359 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_496904 |
| source | MEDLINE; Nature; SWEPUB Freely available online; SpringerLink Journals - AutoHoldings |
| subjects | 13 13/106 13/31 13/89 38 38/109 38/77 42 42/44 631/67/1059/602 631/67/1612/1350 631/67/2329 631/67/71 Adenocarcinoma Adenocarcinoma - metabolism Adenocarcinoma - pathology Adenocarcinoma of Lung Animals Anticancer properties Cancer cells Cancer metastasis Cancer research Cell Proliferation - drug effects Disease Progression Drug resistance Female Gene expression Growth factors Heterogeneity Histology Humanities and Social Sciences Humans letter Ligands Lung cancer Lung diseases Lung Neoplasms - metabolism Lung Neoplasms - pathology Male Medical research Mice multidisciplinary Neoplasm Transplantation Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Perturbation Phenotypes Protein Processing, Post-Translational - drug effects Science Signal transduction Signaling Small Molecule Libraries - pharmacology Stem Cell Niche Stem cell transplantation Stem cells Subpopulations Survival Rate Tumors Wnt protein Wnt Proteins - biosynthesis Wnt Proteins - chemistry Wnt Proteins - metabolism Wnt Signaling Pathway |
| title | A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
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