Heterogeneity and chimerism of endothelial cells revealed by single-cell transcriptome in orthotopic liver tumors
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ORIGINAL PAPER
Heterogeneity and chimerism of endothelial cells revealed by singlecell transcriptome in orthotopic liver tumors Qi Zhao1 · Maria del Pilar Molina‑Portela1 · Asma Parveen1 · Alexander Adler1 · Christina Adler1 · Hock E1 · Wei Wang1 · Min Ni1 · Yi Wei1 · Gurinder Atwal1 · Markus Mohrs1 · Gavin Thurston1 · Alexandra Eichten1 Received: 10 February 2020 / Accepted: 5 May 2020 © The Author(s) 2020
Abstract The liver is a common host organ for cancer, either through lesions that arise in liver epithelial cells [e.g., hepatocellular carcinoma (HCC)] or as a site of metastasis by tumors arising in other organs (e.g., colorectal cancer). However, the changes that occur in liver stromal cells in response to cancer have not been fully characterized, nor has it been determined whether the different sources of liver cancer induce distinct stromal changes. Here, we performed single-cell profiling of liver stromal cells from mouse models of induced spontaneous liver cancer or implanted colorectal liver metastases, with a focus on tumor endothelial cells (ECs). While ECs in liver tissue adjacent to cancerous lesions (so-called adjacent normal) corresponded to liver zonation phenotypes, their transcriptomes were also clearly altered by the presence of a tumor. In comparison, tumor EC transcriptomes show stronger similarities to venous than sinusoidal ECs. Further, tumor ECs, independent of tumor origin, formed distinct clusters displaying conserved “tip-like” or “stalk-like” characteristics, similar to ECs from subcutaneous tumors. However, they also carried liver-specific signatures found in normal liver ECs, suggesting an influence of the host organ on tumor ECs. Our results document gene expression signatures in ECs in liver cancer and show that the host organ, and not the site of tumor origin (liver versus colorectal), is a primary determinant of EC phenotype. In addition, primarily in tumors, we further defined a cluster of chimeric cells that expressed both myeloid and endothelial cell markers and might play a role in tumor angiogenesis. Keywords Single cell transcriptome · Endothelial cell heterogeneity · Kupffer cells · Adjacentnormal tissue · Liver tumor endothelial cells
Introduction The liver is a common host organ for cancer. Tumors in the liver occur either spontaneously through lesions that arise in liver epithelial cells (e.g., hepatocellular and cholangiocarcinomas), or by metastatic spread from primary tumors in other organs (e.g., colorectal cancer). Even though tumors in the liver are quite common, the changes that occur in liver stromal cells in response to tumors have not been well Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09727-9) contains supplementary material, which is available to authorized users. * Alexandra Eichten [email protected] 1
Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA
characterized. Neither has it been determined whether the different cancer types in the l
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