TY - JOUR
T1 - Transcriptional Profiling of Porcine HCC Xenografts Provides Insights Into Tumor Cell Microenvironment Signaling
AU - Patel, Shovik S.
AU - Sandur, Amitha
AU - El-Kebir, Mohammed
AU - Gaba, Ron C.
AU - Schook, Lawrence B.
AU - Schachtschneider, Kyle M.
N1 - This work was supported by the National Institutes of Health – National Cancer Institute (1R21CA219461-01A1), United States Department of Defense (Translational Team Science Award CA150590), the Cooperative Research Program for Agriculture Science & Technology Development (PJ009103) of the Rural Development Administration, Republic of Korea, and the Department of Radiology, University of Illinois at Chicago.
Tsuchida, T., and Friedman, S. L. (2017). Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol 14, 397–411. doi: 10.1038/nrgastro. 2017.38 Turhal, N. S., Sava¸s, B., Ço¸skun, Ö, Ba¸s, E., Karabulut, B., Nart, D., et al. (2015). Prevalence of K-Ras mutations in hepatocellular carcinoma: a turkish oncology group pilot study. Mol. Clin. Oncol. 3, 1275–1279. doi: 10.3892/mco.20 15.633 Warr, A., Affara, N., Aken, B., Beiki, H., Bickhart, D. M., Billis, K., et al. (2020). An improved pig reference genome sequence to enable pig genetics and genomics research. Gigascience 9:giaa051. doi: 10.1093/gigascience/giaa051 Watsky, M. A., Weber, K. T., Sun, Y., and Postlethwaite, A. (2010). New Insights Into the Mechanism of Fibroblast to Myofibroblast Transformation and Associated Pathologies, 1st Edn. Amsterdam: Elsevier Inc, doi: 10.1016/S1937-6448(10)82004-0 Weir, L., Robertson, D., Leigh, I. M., Vass, J. K., and Panteleyev, A. A. (2011). Hypoxia-mediated control of HIF/ARNT machinery in epidermal keratinocytes. Biochim. Biophys. Acta Mol. Cell Res. 1813, 60–72. doi: 10.1016/j. bbamcr.2010.11.014 Whiteside, T. L. (2008). The tumor microenvironment and its role in promoting tumor growth. Oncogene 27, 5904–5912. doi: 10.1038/onc.2008.271 Yang, Z. F., and Poon, R. T. P. (2008). Vascular changes in hepatocellular carcinoma. Anat. Rec. 291, 721–734. doi: 10.1002/ar. 20668 Yeh, M. M., Larson, A. M., Campbell, J. S., Fausto, N., Rulyak, S. J., and Swanson, P. E. (2007). The expression of transforming growth factor-α in cirrhosis, dysplastic nodules, and hepatocellular carcinoma: an immunohistochemical study of 70 cases. Am. J. Surg. Pathol. 31, 681–689. doi: 10.1097/PAS. 0b013e31802ff7aa Zhang, C. Y., Yuan, W. G., He, P., Lei, J. H., and Wang, C. X. (2016). Liver fibrosis and hepatic stellate cells: etiology, pathological hallmarks and therapeutic targets. World J. Gastroenterol. 22, 10512–10522. doi: 10.3748/wjg.v22.i48. 10512 Conflict of Interest: RG receives research funding from the National Insitutes of Health, the United States Department of Defense, Guerbet United States LLC, and Janssen Research Development LLC. KS receives research funding from the National Insitutes of Health, Guerbet United States LLC, and Janssen Research Development LLC. RG, KS, and LS are scientific consultants for Sus Clinicals, Inc.
PY - 2021/4/29
Y1 - 2021/4/29
N2 - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model—a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of KRASG12D and TP53R167H driver mutations—has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors (n = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling in vivo, improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.
AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model—a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of KRASG12D and TP53R167H driver mutations—has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors (n = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling in vivo, improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.
KW - RNA sequencing
KW - hepatic fibrosis
KW - hepatocellular carcinoma
KW - microenvironment
KW - porcine cancer model
KW - xenograft
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U2 - 10.3389/fgene.2021.657330
DO - 10.3389/fgene.2021.657330
M3 - Article
C2 - 33995488
AN - SCOPUS:85105917154
SN - 1664-8021
VL - 12
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 657330
ER -