A single cell atlas of the human liver tumor microenvironment

Hassan Massalha; Keren Bahar Halpern; Samir Abu-Gazala; Tamar Jana; Efi E. Massasa; Andreas E. Moor; Lisa Buchauer; Milena Rozenberg; Eli Pikarsky; Ido Amit; Gideon Zamir; Shalev Itzkovitz

doi:10.15252/msb.20209682

A single cell atlas of the human liver tumor microenvironment

Hassan Massalha, Keren Bahar Halpern, Samir Abu-Gazala, Tamar Jana, Efi E. Massasa, Andreas E. Moor, Lisa Buchauer, Milena Rozenberg, Eli Pikarsky, Ido Amit, Gideon Zamir, Shalev Itzkovitz^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

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.

Original language	American English
Article number	e9682
Journal	Molecular Systems Biology
Volume	16
Issue number	12
DOIs	https://doi.org/10.15252/msb.20209682
State	Published - Dec 2020

Bibliographical note

Funding Information:
We thank Liran Shlush, Itay Tirosh, Ravid Straussman, Lalit Kumar Dubey, Ronen Alon, and Rita Manco for valuable discussions. S.I. is supported by the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Helen and Martin Kimmel Institute for Stem Cell Research grant, the Minerva grant, the Israel Science Foundation grant No. 1486/16, the Broad Institute‐Israel Science Foundation grant No. 2615/18, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program grant No. 768956, the Chan Zuckerberg Initiative grant No. CZF2019‐002434, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. This research was supported by the Israeli Ministry Of Science and Technology (MOST) personal grant to H.M.

Funding Information:
We thank Liran Shlush, Itay Tirosh, Ravid Straussman, Lalit Kumar Dubey, Ronen Alon, and Rita Manco for valuable discussions. S.I. is supported by the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Helen and Martin Kimmel Institute for Stem Cell Research grant, the Minerva grant, the Israel Science Foundation grant No. 1486/16, the Broad Institute-Israel Science Foundation grant No. 2615/18, the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation program grant No. 768956, the Chan Zuckerberg Initiative grant No. CZF2019-002434, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. This research was supported by the Israeli Ministry Of Science and Technology (MOST) personal grant to H.M.

Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

human cell atlas
liver cancer
single cell RNAseq
spatial transcriptomics
tumor-stroma interactions

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/msb.20209682

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title = "A single cell atlas of the human liver tumor microenvironment",

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.",

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author = "Hassan Massalha and {Bahar Halpern}, Keren and Samir Abu-Gazala and Tamar Jana and Massasa, {Efi E.} and Moor, {Andreas E.} and Lisa Buchauer and Milena Rozenberg and Eli Pikarsky and Ido Amit and Gideon Zamir and Shalev Itzkovitz",

note = "Funding Information: We thank Liran Shlush, Itay Tirosh, Ravid Straussman, Lalit Kumar Dubey, Ronen Alon, and Rita Manco for valuable discussions. S.I. is supported by the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Helen and Martin Kimmel Institute for Stem Cell Research grant, the Minerva grant, the Israel Science Foundation grant No. 1486/16, the Broad Institute‐Israel Science Foundation grant No. 2615/18, the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program grant No. 768956, the Chan Zuckerberg Initiative grant No. CZF2019‐002434, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. This research was supported by the Israeli Ministry Of Science and Technology (MOST) personal grant to H.M. Funding Information: We thank Liran Shlush, Itay Tirosh, Ravid Straussman, Lalit Kumar Dubey, Ronen Alon, and Rita Manco for valuable discussions. S.I. is supported by the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Helen and Martin Kimmel Institute for Stem Cell Research grant, the Minerva grant, the Israel Science Foundation grant No. 1486/16, the Broad Institute-Israel Science Foundation grant No. 2615/18, the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation program grant No. 768956, the Chan Zuckerberg Initiative grant No. CZF2019-002434, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. This research was supported by the Israeli Ministry Of Science and Technology (MOST) personal grant to H.M. Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",

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doi = "10.15252/msb.20209682",

language = "American English",

volume = "16",

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AU - Massalha, Hassan

AU - Bahar Halpern, Keren

AU - Abu-Gazala, Samir

AU - Jana, Tamar

AU - Massasa, Efi E.

AU - Moor, Andreas E.

AU - Buchauer, Lisa

AU - Rozenberg, Milena

AU - Pikarsky, Eli

AU - Amit, Ido

AU - Zamir, Gideon

AU - Itzkovitz, Shalev

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N2 - 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.

AB - 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.

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KW - liver cancer

KW - single cell RNAseq

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KW - tumor-stroma interactions

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A single cell atlas of the human liver tumor microenvironment

Abstract

Bibliographical note

Keywords

UN SDGs

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