Dataset Information

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.

ABSTRACT: Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis.

SUBMITTER: Ma L

PROVIDER: S-EPMC6801104 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.

Ma Lichun L Hernandez Maria O MO Zhao Yongmei Y Mehta Monika M Tran Bao B Kelly Michael M Rae Zachary Z Hernandez Jonathan M JM Davis Jeremy L JL Martin Sean P SP Kleiner David E DE Hewitt Stephen M SM Ylaya Kris K Wood Bradford J BJ Greten Tim F TF Wang Xin Wei XW

Cancer cell 20191003 4

Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between h ...[more]

PMID: 31588021

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Project description:The roles of V-ATPase subunits in regulating CRC immune evasion remain unclear. By analyzing the Tumor and Immune System Interaction Database (TISIDB) for correlations between V-ATPases subunits and immune activities, we found that subunit ATP6V0A1 was inversely correlated with immune activities, especially with the proportions of effective or memory T cells in colon adenocarcinoma (COAD), suggesting an immunosuppressive role. With Atp6v0a1/ATP6V0A1 knockdown CRC cells and CRC syngeneic and xenograft mouse models, we confirmed that tumor cell-intrinsic ATP6V0A1 promotes the growth of CRC in an immune-dependent manner. To determine the type of immune cells contributing to ATP6V0A1-mediated immune evasion, we used single-cell transcriptome sequencing (sc-RNA seq) to analyze the ATP6V0A1-edited immune microenvironment in murine MC38 tumors. Holistic immune profiles in Atp6v0a1 knockdown and control MC38 tumors were compared. The results showed that Atp6v0a1 interference in MC38 cells increased the percentages of naïve T, effector T, and memory-like T-2 cells in the total T cell population while decreasing the percentages of exhausted T, Treg, and memory-like T-1 cells. Moreover, the percentages of granulocytes, monocytes, and dendritic cells within the myeloid population were increased in Atp6v0a1 knockdown-derived tumors, whereas the percentage of macrophages was decreased. Of all the immune cell subclusters, memory-like T-2 cells exhibited the most significantly increased cell count ratio in shv0a1 tumors vs. control tumors. In addition, memory-like T-2 cells expressed more effector markers than memory-like T-1 cells. These data suggest that MC38-derived ATP6V0A1 induced immunosuppressive tumor microenvironment (TME) and suppression of the effectiveness of memory-like T cells may play important roles in ATP6V0A1-regulated CRC immune evasion. The study provides directions to investigate the roles and mechanisms of ATP6V0A1 regulating anti-tumor immunity and thus shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

Dataset Information

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.

Publications

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.

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