Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

Lichun Ma; Sophia Heinrich; Limin Wang; Friederike L. Keggenhoff; Subreen Khatib; Marshonna Forgues; Michael Kelly; Stephen M. Hewitt; Areeba Saif; Jonathan M. Hernandez; Donna Mabry; Roman Kloeckner; Tim F. Greten; Jittiporn Chaisaingmongkol; Mathuros Ruchirawat; Jens U. Marquardt; Xin Wei Wang

doi:10.1038/s41467-022-35291-5

Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

Lichun Ma, Sophia Heinrich, Limin Wang, Friederike L. Keggenhoff, Subreen Khatib, Marshonna Forgues, Michael Kelly, Stephen M. Hewitt, Areeba Saif, Jonathan M. Hernandez, Donna Mabry, Roman Kloeckner, Tim F. Greten, Jittiporn Chaisaingmongkol, Mathuros Ruchirawat, Jens U. Marquardt, Xin Wei Wang^*

^*Corresponding author for this work

122 Citations (Scopus)

Abstract

Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumor malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNA-seq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration.

Original language	English
Article number	7533
Journal	Nature Communications
Volume	13
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-022-35291-5
Publication status	Published - 12.2022

Funding

Open Access funding provided by the National Institutes of Health (NIH). We thank members of the Wang laboratory for critical discussions, the patients, families, and nurses for contribution to this study. We also thank Eytan Ruppin and Snorri Thorgeirsson for their critical evaluation of the manuscript. This work was supported by grants (Z01 BC 010877, Z01 BC 010876, Z01 BC 010313, and ZIA BC 011870) from the intramural research program of the Center for Cancer Research, National Cancer Institute of the United States. J.U.M. received funding from the Volkswagen Foundation (Lichtenberg Program) and the Wilhelm-Sander Foundation (2021.089.1).

UN SDGs

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

SDG 3 Good Health and Well-being
SDG 9 Industry, Innovation, and Infrastructure

Research Areas and Centers

Academic Focus: Biomedical Engineering
Centers: University Cancer Center Schleswig-Holstein (UCCSH)
Research Area: Luebeck Integrated Oncology Network (LION)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology
2.21-05 Immunology
2.22-30 Radiology

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10.1038/s41467-022-35291-5

Cite this

Ma, L., Heinrich, S., Wang, L., Keggenhoff, F. L., Khatib, S., Forgues, M., Kelly, M., Hewitt, S. M., Saif, A., Hernandez, J. M., Mabry, D., Kloeckner, R., Greten, T. F., Chaisaingmongkol, J., Ruchirawat, M., Marquardt, J. U., & Wang, X. W. (2022). Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer. Nature Communications, 13(1), Article 7533. https://doi.org/10.1038/s41467-022-35291-5

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title = "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer",

abstract = "Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumor malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNA-seq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration.",

author = "Lichun Ma and Sophia Heinrich and Limin Wang and Keggenhoff, \{Friederike L.\} and Subreen Khatib and Marshonna Forgues and Michael Kelly and Hewitt, \{Stephen M.\} and Areeba Saif and Hernandez, \{Jonathan M.\} and Donna Mabry and Roman Kloeckner and Greten, \{Tim F.\} and Jittiporn Chaisaingmongkol and Mathuros Ruchirawat and Marquardt, \{Jens U.\} and Wang, \{Xin Wei\}",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

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doi = "10.1038/s41467-022-35291-5",

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Ma, L, Heinrich, S, Wang, L, Keggenhoff, FL, Khatib, S, Forgues, M, Kelly, M, Hewitt, SM, Saif, A, Hernandez, JM, Mabry, D, Kloeckner, R, Greten, TF, Chaisaingmongkol, J, Ruchirawat, M, Marquardt, JU & Wang, XW 2022, 'Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer', Nature Communications, vol. 13, no. 1, 7533. https://doi.org/10.1038/s41467-022-35291-5

TY - JOUR

T1 - Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

AU - Ma, Lichun

AU - Heinrich, Sophia

AU - Wang, Limin

AU - Keggenhoff, Friederike L.

AU - Khatib, Subreen

AU - Forgues, Marshonna

AU - Kelly, Michael

AU - Hewitt, Stephen M.

AU - Saif, Areeba

AU - Hernandez, Jonathan M.

AU - Mabry, Donna

AU - Kloeckner, Roman

AU - Greten, Tim F.

AU - Chaisaingmongkol, Jittiporn

AU - Ruchirawat, Mathuros

AU - Marquardt, Jens U.

AU - Wang, Xin Wei

PY - 2022/12

Y1 - 2022/12

N2 - Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumor malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNA-seq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration.

AB - Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with the tumor microenvironment which collectively drives tumorigenesis. However, an appearance of cellular and molecular heterogeneity creates a challenge to define molecular features linked to tumor malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis of seven liver cancer patients (four hepatocellular carcinoma, HCC and three intrahepatic cholangiocarcinoma, iCCA). We identify cellular dynamics of malignant cells and their communication networks with tumor-associated immune cells, which are validated using additional scRNA-seq data of 25 HCC and 12 iCCA patients as a stable fingerprint embedded in a malignant ecosystem representing features of tumor aggressiveness. We further validate the top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 and SPP1-PTGER4 between tumor cells and macrophages) associated with unique transcriptome in additional 542 HCC patients. Our study unveils stable molecular networks of malignant ecosystems, which may open a path for therapeutic exploration.

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ER -

Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

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