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 and Xin Wei Wang ()
Additional contact information
Lichun Ma: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Sophia Heinrich: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Limin Wang: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Friederike L. Keggenhoff: Johannes Gutenberg University
Subreen Khatib: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Marshonna Forgues: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute
Michael Kelly: Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc.
Stephen M. Hewitt: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute
Areeba Saif: Surgical Oncology Program, Center for Cancer Research, National Cancer Institute
Jonathan M. Hernandez: Surgical Oncology Program, Center for Cancer Research, National Cancer Institute
Donna Mabry: Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute
Roman Kloeckner: Johannes Gutenberg University
Tim F. Greten: Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute
Jittiporn Chaisaingmongkol: Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute
Mathuros Ruchirawat: Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute
Jens U. Marquardt: Johannes Gutenberg University
Xin Wei Wang: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35291-5

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