Loading…

The drug-induced phenotypic landscape of colorectal cancer organoids

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2022-06, Vol.13 (1), p.3135-3135, Article 3135
Main Authors: Betge, Johannes, Rindtorff, Niklas, Sauer, Jan, Rauscher, Benedikt, Dingert, Clara, Gaitantzi, Haristi, Herweck, Frank, Srour-Mhanna, Kauthar, Miersch, Thilo, Valentini, Erica, Boonekamp, Kim E., Hauber, Veronika, Gutting, Tobias, Frank, Larissa, Belle, Sebastian, Gaiser, Timo, Buchholz, Inga, Jesenofsky, Ralf, Härtel, Nicolai, Zhan, Tianzuo, Fischer, Bernd, Breitkopf-Heinlein, Katja, Burgermeister, Elke, Ebert, Matthias P., Boutros, Michael
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183
cites cdi_FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183
container_end_page 3135
container_issue 1
container_start_page 3135
container_title Nature communications
container_volume 13
creator Betge, Johannes
Rindtorff, Niklas
Sauer, Jan
Rauscher, Benedikt
Dingert, Clara
Gaitantzi, Haristi
Herweck, Frank
Srour-Mhanna, Kauthar
Miersch, Thilo
Valentini, Erica
Boonekamp, Kim E.
Hauber, Veronika
Gutting, Tobias
Frank, Larissa
Belle, Sebastian
Gaiser, Timo
Buchholz, Inga
Jesenofsky, Ralf
Härtel, Nicolai
Zhan, Tianzuo
Fischer, Bernd
Breitkopf-Heinlein, Katja
Burgermeister, Elke
Ebert, Matthias P.
Boutros, Michael
description Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5 , while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
doi_str_mv 10.1038/s41467-022-30722-9
format article
fullrecord <record><control><sourceid>proquest_doaj_</sourceid><recordid>TN_cdi_doaj_primary_oai_doaj_org_article_781b445e149e41f2a3b65e3af8beee8f</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_781b445e149e41f2a3b65e3af8beee8f</doaj_id><sourcerecordid>2674001464</sourcerecordid><originalsourceid>FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183</originalsourceid><addsrcrecordid>eNp9kctO3TAQhi3UChDlBbqoInXTTYovY8fZVKqAFiSkbuja8mVyTo5y4tROKvH2GEIpdFEvbMvzzT_j-Ql5z-hnRoU-y8BANTXlvBa0KXt7QI45BVazhos3L-5H5DTnHS1LtEwDHJIjIZXSjOpjcnG7xSqkZVP3Y1g8hmra4hjnu6n31WDHkL2dsIpd5eMQE_rZDpW3o8dUxbSxY-xDfkfednbIePp0npCf3y5vz6_qmx_fr8-_3tReAp1rRLDaUWmV423Xam-plFxDcDRYph16T1VnnXIgIQihFDAdQGjpBCqmxQm5XnVDtDszpX5v052JtjePD6UfY9Pc-wFNo5kDkMigRWAdt8IpicJ2pQyi7orWl1VrWtweg8dxTnZ4Jfo6MvZbs4m_Tcsa2jBVBD49CaT4a8E8m32fPQ5laBiXbLhqgNJiEhT04z_oLi5pLKN6oARIWqZQKL5SPsWcE3bPzTBqHjw3q-emeG4ePTdtSfrw8hvPKX8cLoBYgVxC4wbT39r_kb0HnIS3NQ</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2673450284</pqid></control><display><type>article</type><title>The drug-induced phenotypic landscape of colorectal cancer organoids</title><source>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</source><source>PubMed Central Free</source><source>Nature</source><source>Springer Nature - nature.com Journals - Fully Open Access</source><creator>Betge, Johannes ; Rindtorff, Niklas ; Sauer, Jan ; Rauscher, Benedikt ; Dingert, Clara ; Gaitantzi, Haristi ; Herweck, Frank ; Srour-Mhanna, Kauthar ; Miersch, Thilo ; Valentini, Erica ; Boonekamp, Kim E. ; Hauber, Veronika ; Gutting, Tobias ; Frank, Larissa ; Belle, Sebastian ; Gaiser, Timo ; Buchholz, Inga ; Jesenofsky, Ralf ; Härtel, Nicolai ; Zhan, Tianzuo ; Fischer, Bernd ; Breitkopf-Heinlein, Katja ; Burgermeister, Elke ; Ebert, Matthias P. ; Boutros, Michael</creator><creatorcontrib>Betge, Johannes ; Rindtorff, Niklas ; Sauer, Jan ; Rauscher, Benedikt ; Dingert, Clara ; Gaitantzi, Haristi ; Herweck, Frank ; Srour-Mhanna, Kauthar ; Miersch, Thilo ; Valentini, Erica ; Boonekamp, Kim E. ; Hauber, Veronika ; Gutting, Tobias ; Frank, Larissa ; Belle, Sebastian ; Gaiser, Timo ; Buchholz, Inga ; Jesenofsky, Ralf ; Härtel, Nicolai ; Zhan, Tianzuo ; Fischer, Bernd ; Breitkopf-Heinlein, Katja ; Burgermeister, Elke ; Ebert, Matthias P. ; Boutros, Michael</creatorcontrib><description>Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with &gt;500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5 , while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-022-30722-9</identifier><identifier>PMID: 35668108</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14 ; 14/19 ; 14/56 ; 45 ; 45/47 ; 49/47 ; 631/154/1435/2417 ; 631/67/1504/1885 ; 631/67/69 ; 631/67/70 ; 64 ; 692/4028/67/1504 ; 96 ; 96/47 ; 96/63 ; Cancer ; Colorectal cancer ; Colorectal carcinoma ; Heterogeneity ; Humanities and Social Sciences ; Insulin-like growth factor I ; Modelling ; Morphology ; multidisciplinary ; Organoids ; Phenotypes ; Receptors ; Science ; Science (multidisciplinary) ; Signaling ; TOR protein ; Tumors</subject><ispartof>Nature communications, 2022-06, Vol.13 (1), p.3135-3135, Article 3135</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183</citedby><cites>FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183</cites><orcidid>0000-0001-9549-1866 ; 0000-0002-1814-4796 ; 0000-0001-9437-2099 ; 0000-0002-4969-5697 ; 0000-0003-3602-4170 ; 0000-0003-3228-5138 ; 0000-0002-9458-817X ; 0000-0001-8460-1644</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2673450284/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2673450284?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35668108$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Betge, Johannes</creatorcontrib><creatorcontrib>Rindtorff, Niklas</creatorcontrib><creatorcontrib>Sauer, Jan</creatorcontrib><creatorcontrib>Rauscher, Benedikt</creatorcontrib><creatorcontrib>Dingert, Clara</creatorcontrib><creatorcontrib>Gaitantzi, Haristi</creatorcontrib><creatorcontrib>Herweck, Frank</creatorcontrib><creatorcontrib>Srour-Mhanna, Kauthar</creatorcontrib><creatorcontrib>Miersch, Thilo</creatorcontrib><creatorcontrib>Valentini, Erica</creatorcontrib><creatorcontrib>Boonekamp, Kim E.</creatorcontrib><creatorcontrib>Hauber, Veronika</creatorcontrib><creatorcontrib>Gutting, Tobias</creatorcontrib><creatorcontrib>Frank, Larissa</creatorcontrib><creatorcontrib>Belle, Sebastian</creatorcontrib><creatorcontrib>Gaiser, Timo</creatorcontrib><creatorcontrib>Buchholz, Inga</creatorcontrib><creatorcontrib>Jesenofsky, Ralf</creatorcontrib><creatorcontrib>Härtel, Nicolai</creatorcontrib><creatorcontrib>Zhan, Tianzuo</creatorcontrib><creatorcontrib>Fischer, Bernd</creatorcontrib><creatorcontrib>Breitkopf-Heinlein, Katja</creatorcontrib><creatorcontrib>Burgermeister, Elke</creatorcontrib><creatorcontrib>Ebert, Matthias P.</creatorcontrib><creatorcontrib>Boutros, Michael</creatorcontrib><title>The drug-induced phenotypic landscape of colorectal cancer organoids</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with &gt;500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5 , while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.</description><subject>14</subject><subject>14/19</subject><subject>14/56</subject><subject>45</subject><subject>45/47</subject><subject>49/47</subject><subject>631/154/1435/2417</subject><subject>631/67/1504/1885</subject><subject>631/67/69</subject><subject>631/67/70</subject><subject>64</subject><subject>692/4028/67/1504</subject><subject>96</subject><subject>96/47</subject><subject>96/63</subject><subject>Cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Heterogeneity</subject><subject>Humanities and Social Sciences</subject><subject>Insulin-like growth factor I</subject><subject>Modelling</subject><subject>Morphology</subject><subject>multidisciplinary</subject><subject>Organoids</subject><subject>Phenotypes</subject><subject>Receptors</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signaling</subject><subject>TOR protein</subject><subject>Tumors</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp9kctO3TAQhi3UChDlBbqoInXTTYovY8fZVKqAFiSkbuja8mVyTo5y4tROKvH2GEIpdFEvbMvzzT_j-Ql5z-hnRoU-y8BANTXlvBa0KXt7QI45BVazhos3L-5H5DTnHS1LtEwDHJIjIZXSjOpjcnG7xSqkZVP3Y1g8hmra4hjnu6n31WDHkL2dsIpd5eMQE_rZDpW3o8dUxbSxY-xDfkfednbIePp0npCf3y5vz6_qmx_fr8-_3tReAp1rRLDaUWmV423Xam-plFxDcDRYph16T1VnnXIgIQihFDAdQGjpBCqmxQm5XnVDtDszpX5v052JtjePD6UfY9Pc-wFNo5kDkMigRWAdt8IpicJ2pQyi7orWl1VrWtweg8dxTnZ4Jfo6MvZbs4m_Tcsa2jBVBD49CaT4a8E8m32fPQ5laBiXbLhqgNJiEhT04z_oLi5pLKN6oARIWqZQKL5SPsWcE3bPzTBqHjw3q-emeG4ePTdtSfrw8hvPKX8cLoBYgVxC4wbT39r_kb0HnIS3NQ</recordid><startdate>20220606</startdate><enddate>20220606</enddate><creator>Betge, Johannes</creator><creator>Rindtorff, Niklas</creator><creator>Sauer, Jan</creator><creator>Rauscher, Benedikt</creator><creator>Dingert, Clara</creator><creator>Gaitantzi, Haristi</creator><creator>Herweck, Frank</creator><creator>Srour-Mhanna, Kauthar</creator><creator>Miersch, Thilo</creator><creator>Valentini, Erica</creator><creator>Boonekamp, Kim E.</creator><creator>Hauber, Veronika</creator><creator>Gutting, Tobias</creator><creator>Frank, Larissa</creator><creator>Belle, Sebastian</creator><creator>Gaiser, Timo</creator><creator>Buchholz, Inga</creator><creator>Jesenofsky, Ralf</creator><creator>Härtel, Nicolai</creator><creator>Zhan, Tianzuo</creator><creator>Fischer, Bernd</creator><creator>Breitkopf-Heinlein, Katja</creator><creator>Burgermeister, Elke</creator><creator>Ebert, Matthias P.</creator><creator>Boutros, Michael</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><general>Nature Portfolio</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9549-1866</orcidid><orcidid>https://orcid.org/0000-0002-1814-4796</orcidid><orcidid>https://orcid.org/0000-0001-9437-2099</orcidid><orcidid>https://orcid.org/0000-0002-4969-5697</orcidid><orcidid>https://orcid.org/0000-0003-3602-4170</orcidid><orcidid>https://orcid.org/0000-0003-3228-5138</orcidid><orcidid>https://orcid.org/0000-0002-9458-817X</orcidid><orcidid>https://orcid.org/0000-0001-8460-1644</orcidid></search><sort><creationdate>20220606</creationdate><title>The drug-induced phenotypic landscape of colorectal cancer organoids</title><author>Betge, Johannes ; Rindtorff, Niklas ; Sauer, Jan ; Rauscher, Benedikt ; Dingert, Clara ; Gaitantzi, Haristi ; Herweck, Frank ; Srour-Mhanna, Kauthar ; Miersch, Thilo ; Valentini, Erica ; Boonekamp, Kim E. ; Hauber, Veronika ; Gutting, Tobias ; Frank, Larissa ; Belle, Sebastian ; Gaiser, Timo ; Buchholz, Inga ; Jesenofsky, Ralf ; Härtel, Nicolai ; Zhan, Tianzuo ; Fischer, Bernd ; Breitkopf-Heinlein, Katja ; Burgermeister, Elke ; Ebert, Matthias P. ; Boutros, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>14</topic><topic>14/19</topic><topic>14/56</topic><topic>45</topic><topic>45/47</topic><topic>49/47</topic><topic>631/154/1435/2417</topic><topic>631/67/1504/1885</topic><topic>631/67/69</topic><topic>631/67/70</topic><topic>64</topic><topic>692/4028/67/1504</topic><topic>96</topic><topic>96/47</topic><topic>96/63</topic><topic>Cancer</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Heterogeneity</topic><topic>Humanities and Social Sciences</topic><topic>Insulin-like growth factor I</topic><topic>Modelling</topic><topic>Morphology</topic><topic>multidisciplinary</topic><topic>Organoids</topic><topic>Phenotypes</topic><topic>Receptors</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signaling</topic><topic>TOR protein</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Betge, Johannes</creatorcontrib><creatorcontrib>Rindtorff, Niklas</creatorcontrib><creatorcontrib>Sauer, Jan</creatorcontrib><creatorcontrib>Rauscher, Benedikt</creatorcontrib><creatorcontrib>Dingert, Clara</creatorcontrib><creatorcontrib>Gaitantzi, Haristi</creatorcontrib><creatorcontrib>Herweck, Frank</creatorcontrib><creatorcontrib>Srour-Mhanna, Kauthar</creatorcontrib><creatorcontrib>Miersch, Thilo</creatorcontrib><creatorcontrib>Valentini, Erica</creatorcontrib><creatorcontrib>Boonekamp, Kim E.</creatorcontrib><creatorcontrib>Hauber, Veronika</creatorcontrib><creatorcontrib>Gutting, Tobias</creatorcontrib><creatorcontrib>Frank, Larissa</creatorcontrib><creatorcontrib>Belle, Sebastian</creatorcontrib><creatorcontrib>Gaiser, Timo</creatorcontrib><creatorcontrib>Buchholz, Inga</creatorcontrib><creatorcontrib>Jesenofsky, Ralf</creatorcontrib><creatorcontrib>Härtel, Nicolai</creatorcontrib><creatorcontrib>Zhan, Tianzuo</creatorcontrib><creatorcontrib>Fischer, Bernd</creatorcontrib><creatorcontrib>Breitkopf-Heinlein, Katja</creatorcontrib><creatorcontrib>Burgermeister, Elke</creatorcontrib><creatorcontrib>Ebert, Matthias P.</creatorcontrib><creatorcontrib>Boutros, Michael</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Betge, Johannes</au><au>Rindtorff, Niklas</au><au>Sauer, Jan</au><au>Rauscher, Benedikt</au><au>Dingert, Clara</au><au>Gaitantzi, Haristi</au><au>Herweck, Frank</au><au>Srour-Mhanna, Kauthar</au><au>Miersch, Thilo</au><au>Valentini, Erica</au><au>Boonekamp, Kim E.</au><au>Hauber, Veronika</au><au>Gutting, Tobias</au><au>Frank, Larissa</au><au>Belle, Sebastian</au><au>Gaiser, Timo</au><au>Buchholz, Inga</au><au>Jesenofsky, Ralf</au><au>Härtel, Nicolai</au><au>Zhan, Tianzuo</au><au>Fischer, Bernd</au><au>Breitkopf-Heinlein, Katja</au><au>Burgermeister, Elke</au><au>Ebert, Matthias P.</au><au>Boutros, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The drug-induced phenotypic landscape of colorectal cancer organoids</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2022-06-06</date><risdate>2022</risdate><volume>13</volume><issue>1</issue><spage>3135</spage><epage>3135</epage><pages>3135-3135</pages><artnum>3135</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with &gt;500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5 , while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>35668108</pmid><doi>10.1038/s41467-022-30722-9</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-9549-1866</orcidid><orcidid>https://orcid.org/0000-0002-1814-4796</orcidid><orcidid>https://orcid.org/0000-0001-9437-2099</orcidid><orcidid>https://orcid.org/0000-0002-4969-5697</orcidid><orcidid>https://orcid.org/0000-0003-3602-4170</orcidid><orcidid>https://orcid.org/0000-0003-3228-5138</orcidid><orcidid>https://orcid.org/0000-0002-9458-817X</orcidid><orcidid>https://orcid.org/0000-0001-8460-1644</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2041-1723
ispartof Nature communications, 2022-06, Vol.13 (1), p.3135-3135, Article 3135
issn 2041-1723
2041-1723
language eng
recordid cdi_doaj_primary_oai_doaj_org_article_781b445e149e41f2a3b65e3af8beee8f
source Publicly Available Content Database (Proquest) (PQ_SDU_P3); PubMed Central Free; Nature; Springer Nature - nature.com Journals - Fully Open Access
subjects 14
14/19
14/56
45
45/47
49/47
631/154/1435/2417
631/67/1504/1885
631/67/69
631/67/70
64
692/4028/67/1504
96
96/47
96/63
Cancer
Colorectal cancer
Colorectal carcinoma
Heterogeneity
Humanities and Social Sciences
Insulin-like growth factor I
Modelling
Morphology
multidisciplinary
Organoids
Phenotypes
Receptors
Science
Science (multidisciplinary)
Signaling
TOR protein
Tumors
title The drug-induced phenotypic landscape of colorectal cancer organoids
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T16%3A37%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20drug-induced%20phenotypic%20landscape%20of%20colorectal%20cancer%20organoids&rft.jtitle=Nature%20communications&rft.au=Betge,%20Johannes&rft.date=2022-06-06&rft.volume=13&rft.issue=1&rft.spage=3135&rft.epage=3135&rft.pages=3135-3135&rft.artnum=3135&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/s41467-022-30722-9&rft_dat=%3Cproquest_doaj_%3E2674001464%3C/proquest_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c540t-ee4a8b05a6b29f98ca055284db0da18becc06fab6b454d3366418d4385b3e6183%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2673450284&rft_id=info:pmid/35668108&rfr_iscdi=true