Abstract 3785: Loss of vacuolar ATPase in hematopoietic stem cells promotes breast tumor progression and pathogenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 13_Supplement; p. 3785
• Main Authors: Sahoo, Manoranjan, Katara, Gajendra K., Bilal, Mahamood Y., Fleetwood, Sara, Kulshrestha, Arpita, Ibrahim, Safaa A., Beaman, Kenneth D.
• Format: Journal Article
• Language: English
• Published: 01.07.2018
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-3785

Abstract Vacuolar ATPase (V-ATPase) is expressed intracellularly on vesicular membranes, and controls intracellular pH and acidification of various intracellular vesicles. Most cancer cells express V-ATPase on their cell surface where they appear to acidify the extracellular environment and help cancer cells to metastasize. We have previously demonstrated that the a2 isoform of V-ATPase (a2V) of mammary epithelial cells plays a key role during breast tumor progression and metastasis. However, the role of a2V of hematopoietic stem cells during breast tumor pathogenesis is not known. Therefore, to understand the role of a2V in hematopoietic stem cells during breast tumor progression, we conditionally knocked out a2V (cKO) from the hematopoietic stem cells of mice. We observed that deletion of a2V leads to a significant reduction of CD4+ and CD8+ T cells in the periphery and spleen of the a2V cKO mice compared to control mice. We hypothesized that reduction of helper CD4+ cells, or cytotoxic CD8+ T cells would result in larger and faster-growing tumors in the a2V-cKO mice. After implantation of a syngeneic tumor cell line (E0771) in the breast tissue of mice, we observed that deletion of a2V led to larger and faster-growing breast tumors compared to control mice. Further investigation of the tumor microenvironment revealed that there was a significant reduction in percentage of CD4+ and CD8+ T cells in the a2V-cKO mice compared to control mice. Targeted RNAseq of tumor microenvironment demonstrated that out of 499 genes that were analyzed, only 3 genes were significantly upregulated while 144 genes were significantly downregulated in the a2V cKO mice. The 144 downregulated genes included genes for pro-inflammatory cytokines, T cell specific genes, death receptors and proapoptotic genes. Collectively, these results demonstrate that deletion of a2V from the hematopoietic stem cells leads to a decrease in CD4+ and CD8+ T cells in the periphery, which results in a faster-growing and larger breast tumor. Further study is needed to understand the relative contribution of CD4+ or CD8+ T cells during breast tumor pathogenesis. Citation Format: Manoranjan Sahoo, Gajendra K. Katara, Mahamood Y. Bilal, Sara Fleetwood, Arpita Kulshrestha, Safaa A. Ibrahim, Kenneth D. Beaman. Loss of vacuolar ATPase in hematopoietic stem cells promotes breast tumor progression and pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3785.