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A single cell atlas of the human liver tumor microenvironment
Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pa...
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Published in: | Molecular systems biology 2020-12, Vol.16 (12), p.e9682-n/a |
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creator | Massalha, Hassan Bahar Halpern, Keren Abu‐Gazala, Samir Jana, Tamar Massasa, Efi E Moor, Andreas E Buchauer, Lisa Rozenberg, Milena Pikarsky, Eli Amit, Ido Zamir, Gideon Itzkovitz, Shalev |
description | Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA‐sequencing and spatial analysis of malignant and adjacent non‐malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient‐independent expression programs, and reconstruct a ligand–receptor map that highlights recurring tumor–stroma interactions. By combining transcriptomics of laser‐capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non‐malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.
SYNOPSIS
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.
A single cell atlas of the malignant and adjacent non‐malignant human liver is presented.
Recurring stromal cell gene expression signatures are found in liver metastases and cholangiocarcinomas.
Tumor and stromal cells communicate through a conserved ligand‐receptor interaction network.
Spatial transcriptomics reveal zonated expression patterns in the malignant and non‐malignant liver.
Graphical Abstract
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue. |
doi_str_mv | 10.15252/msb.20209682 |
format | article |
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SYNOPSIS
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.
A single cell atlas of the malignant and adjacent non‐malignant human liver is presented.
Recurring stromal cell gene expression signatures are found in liver metastases and cholangiocarcinomas.
Tumor and stromal cells communicate through a conserved ligand‐receptor interaction network.
Spatial transcriptomics reveal zonated expression patterns in the malignant and non‐malignant liver.
Graphical Abstract
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.</description><identifier>ISSN: 1744-4292</identifier><identifier>EISSN: 1744-4292</identifier><identifier>DOI: 10.15252/msb.20209682</identifier><identifier>PMID: 33332768</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Anatomy, Artistic ; Animals ; Atlases as Topic ; Cholangiocarcinoma ; EMBO03 ; EMBO22 ; Endothelial Cells - metabolism ; Fibroblasts ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Gene sequencing ; Hepatocytes ; Hepatocytes - metabolism ; human cell atlas ; Humans ; Liver ; Liver cancer ; Liver Neoplasms - genetics ; Liver Neoplasms - immunology ; Liver Neoplasms - pathology ; Lymphocytes ; Metastases ; Metastasis ; Mice ; Patients ; Ribonucleic acid ; RNA ; single cell RNAseq ; Single-Cell Analysis ; Smooth muscle ; Spatial analysis ; Spatial distribution ; spatial transcriptomics ; Stromal cells ; Transcriptomics ; Tumor cells ; Tumor microenvironment ; Tumor Microenvironment - genetics ; Tumors ; tumor‐stroma interactions ; Zonation</subject><ispartof>Molecular systems biology, 2020-12, Vol.16 (12), p.e9682-n/a</ispartof><rights>The Author(s) 2020</rights><rights>2020 The Authors. Published under the terms of the CC BY 4.0 license</rights><rights>2020 The Authors. Published under the terms of the CC BY 4.0 license.</rights><rights>2020. 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-c5952-240b225d875e6be5344698b5d0d0acf1eaef672b9979eded3ee6a122d1cfca343</citedby><cites>FETCH-LOGICAL-c5952-240b225d875e6be5344698b5d0d0acf1eaef672b9979eded3ee6a122d1cfca343</cites><orcidid>0000-0001-8715-8449 ; 0000-0003-0685-2522 ; 0000-0002-4722-8390 ; 0000-0002-9923-6878</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746227/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2598875223?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,11562,25753,27924,27925,37012,37013,44590,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33332768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Massalha, Hassan</creatorcontrib><creatorcontrib>Bahar Halpern, Keren</creatorcontrib><creatorcontrib>Abu‐Gazala, Samir</creatorcontrib><creatorcontrib>Jana, Tamar</creatorcontrib><creatorcontrib>Massasa, Efi E</creatorcontrib><creatorcontrib>Moor, Andreas E</creatorcontrib><creatorcontrib>Buchauer, Lisa</creatorcontrib><creatorcontrib>Rozenberg, Milena</creatorcontrib><creatorcontrib>Pikarsky, Eli</creatorcontrib><creatorcontrib>Amit, Ido</creatorcontrib><creatorcontrib>Zamir, Gideon</creatorcontrib><creatorcontrib>Itzkovitz, Shalev</creatorcontrib><title>A single cell atlas of the human liver tumor microenvironment</title><title>Molecular systems biology</title><addtitle>Mol Syst Biol</addtitle><addtitle>Mol Syst Biol</addtitle><description>Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA‐sequencing and spatial analysis of malignant and adjacent non‐malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient‐independent expression programs, and reconstruct a ligand–receptor map that highlights recurring tumor–stroma interactions. By combining transcriptomics of laser‐capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non‐malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.
SYNOPSIS
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.
A single cell atlas of the malignant and adjacent non‐malignant human liver is presented.
Recurring stromal cell gene expression signatures are found in liver metastases and cholangiocarcinomas.
Tumor and stromal cells communicate through a conserved ligand‐receptor interaction network.
Spatial transcriptomics reveal zonated expression patterns in the malignant and non‐malignant liver.
Graphical Abstract
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.</description><subject>Anatomy, Artistic</subject><subject>Animals</subject><subject>Atlases as Topic</subject><subject>Cholangiocarcinoma</subject><subject>EMBO03</subject><subject>EMBO22</subject><subject>Endothelial Cells - metabolism</subject><subject>Fibroblasts</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Gene sequencing</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>human cell atlas</subject><subject>Humans</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - immunology</subject><subject>Liver Neoplasms - pathology</subject><subject>Lymphocytes</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Patients</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>single cell RNAseq</subject><subject>Single-Cell Analysis</subject><subject>Smooth muscle</subject><subject>Spatial analysis</subject><subject>Spatial distribution</subject><subject>spatial transcriptomics</subject><subject>Stromal cells</subject><subject>Transcriptomics</subject><subject>Tumor cells</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - genetics</subject><subject>Tumors</subject><subject>tumor‐stroma interactions</subject><subject>Zonation</subject><issn>1744-4292</issn><issn>1744-4292</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp9kktv1DAUhSMEog9YskWR2LDJYF-_4gVIpSpQqYgFsLYc52bGoyQudjKo_x63acsUoXpjy_7u8bmPonhFyYoKEPBuSM0KCBAta3hSHFLFecVBw9O980FxlNKWEFbTGp4XBywvULI-LN6flMmP6x5Lh31f2qm3qQxdOW2w3MyDHcve7zCW0zyEWA7exYDjzscwDjhOL4pnne0Tvrzdj4ufn85-nH6pLr59Pj89uaic0AIq4KQBEG2tBMoGBeNc6roRLWmJdR1Fi51U0GitNLbYMkRpKUBLXecs4-y4OF9022C35jL6wcYrE6w3Nxchro2Nk3c9GkdbyloEhVTkb1hTI5OEWqFr5rRUWevDonU5NwO2LqcRbf9A9OHL6DdmHXZGKS4BrgXe3grE8GvGNJnBp-vq2RHDnAxwRbkktRYZffMPug1zHHOpDGRDuR4A7FGKq9wqRaTMVLVQuQUpRezuLVNibkbB5FEwd6OQ-df7ed7Td73PgFyA377Hq8fVzNfvH_eUV0tgyjHjGuNfv_-38gcOEcyq</recordid><startdate>202012</startdate><enddate>202012</enddate><creator>Massalha, Hassan</creator><creator>Bahar Halpern, Keren</creator><creator>Abu‐Gazala, Samir</creator><creator>Jana, Tamar</creator><creator>Massasa, Efi E</creator><creator>Moor, Andreas E</creator><creator>Buchauer, Lisa</creator><creator>Rozenberg, Milena</creator><creator>Pikarsky, Eli</creator><creator>Amit, Ido</creator><creator>Zamir, Gideon</creator><creator>Itzkovitz, Shalev</creator><general>Nature Publishing Group UK</general><general>EMBO Press</general><general>John Wiley and Sons Inc</general><general>Springer Nature</general><scope>C6C</scope><scope>24P</scope><scope>WIN</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>3V.</scope><scope>7QL</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PADUT</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-8715-8449</orcidid><orcidid>https://orcid.org/0000-0003-0685-2522</orcidid><orcidid>https://orcid.org/0000-0002-4722-8390</orcidid><orcidid>https://orcid.org/0000-0002-9923-6878</orcidid></search><sort><creationdate>202012</creationdate><title>A single cell atlas of the human liver tumor microenvironment</title><author>Massalha, Hassan ; Bahar Halpern, Keren ; Abu‐Gazala, Samir ; Jana, Tamar ; Massasa, Efi E ; Moor, Andreas E ; Buchauer, Lisa ; Rozenberg, Milena ; Pikarsky, Eli ; Amit, Ido ; Zamir, Gideon ; Itzkovitz, Shalev</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5952-240b225d875e6be5344698b5d0d0acf1eaef672b9979eded3ee6a122d1cfca343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Anatomy, Artistic</topic><topic>Animals</topic><topic>Atlases as Topic</topic><topic>Cholangiocarcinoma</topic><topic>EMBO03</topic><topic>EMBO22</topic><topic>Endothelial Cells - metabolism</topic><topic>Fibroblasts</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Regulatory Networks</topic><topic>Gene sequencing</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>human cell atlas</topic><topic>Humans</topic><topic>Liver</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - immunology</topic><topic>Liver Neoplasms - pathology</topic><topic>Lymphocytes</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Patients</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>single cell RNAseq</topic><topic>Single-Cell Analysis</topic><topic>Smooth muscle</topic><topic>Spatial analysis</topic><topic>Spatial distribution</topic><topic>spatial transcriptomics</topic><topic>Stromal cells</topic><topic>Transcriptomics</topic><topic>Tumor cells</topic><topic>Tumor microenvironment</topic><topic>Tumor Microenvironment - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>Molecular systems biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Massalha, Hassan</au><au>Bahar Halpern, Keren</au><au>Abu‐Gazala, Samir</au><au>Jana, Tamar</au><au>Massasa, Efi E</au><au>Moor, Andreas E</au><au>Buchauer, Lisa</au><au>Rozenberg, Milena</au><au>Pikarsky, Eli</au><au>Amit, Ido</au><au>Zamir, Gideon</au><au>Itzkovitz, Shalev</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A single cell atlas of the human liver tumor microenvironment</atitle><jtitle>Molecular systems biology</jtitle><stitle>Mol Syst Biol</stitle><addtitle>Mol Syst Biol</addtitle><date>2020-12</date><risdate>2020</risdate><volume>16</volume><issue>12</issue><spage>e9682</spage><epage>n/a</epage><pages>e9682-n/a</pages><issn>1744-4292</issn><eissn>1744-4292</eissn><abstract>Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA‐sequencing and spatial analysis of malignant and adjacent non‐malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient‐independent expression programs, and reconstruct a ligand–receptor map that highlights recurring tumor–stroma interactions. By combining transcriptomics of laser‐capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non‐malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.
SYNOPSIS
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.
A single cell atlas of the malignant and adjacent non‐malignant human liver is presented.
Recurring stromal cell gene expression signatures are found in liver metastases and cholangiocarcinomas.
Tumor and stromal cells communicate through a conserved ligand‐receptor interaction network.
Spatial transcriptomics reveal zonated expression patterns in the malignant and non‐malignant liver.
Graphical Abstract
Single cell transcriptomics and spatial methods are used to generate a cell atlas of the human liver tumor microenvironment, exposing recurring tumor‐stroma interactions and zonation patterns in the healthy and malignant tissue.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33332768</pmid><doi>10.15252/msb.20209682</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-8715-8449</orcidid><orcidid>https://orcid.org/0000-0003-0685-2522</orcidid><orcidid>https://orcid.org/0000-0002-4722-8390</orcidid><orcidid>https://orcid.org/0000-0002-9923-6878</orcidid><oa>free_for_read</oa></addata></record> |
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source | Open Access: Wiley-Blackwell Open Access Journals; Publicly Available Content Database; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Anatomy, Artistic Animals Atlases as Topic Cholangiocarcinoma EMBO03 EMBO22 Endothelial Cells - metabolism Fibroblasts Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Regulatory Networks Gene sequencing Hepatocytes Hepatocytes - metabolism human cell atlas Humans Liver Liver cancer Liver Neoplasms - genetics Liver Neoplasms - immunology Liver Neoplasms - pathology Lymphocytes Metastases Metastasis Mice Patients Ribonucleic acid RNA single cell RNAseq Single-Cell Analysis Smooth muscle Spatial analysis Spatial distribution spatial transcriptomics Stromal cells Transcriptomics Tumor cells Tumor microenvironment Tumor Microenvironment - genetics Tumors tumor‐stroma interactions Zonation |
title | A single cell atlas of the human liver tumor microenvironment |
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