MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC
The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253120301979 |
| _version_ | 1818341889351352320 |
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| author | Renumathy Dhanasekaran Jangho Park Alekesey Yevtodiyenko David I. Bellovin Stacey J. Adam Anand Rajan KD Meital Gabay Hanan Fernando Julia Arzeno Vinodhini Arjunan Sergei Gryanzov Dean W. Felsher |
| author_facet | Renumathy Dhanasekaran Jangho Park Alekesey Yevtodiyenko David I. Bellovin Stacey J. Adam Anand Rajan KD Meital Gabay Hanan Fernando Julia Arzeno Vinodhini Arjunan Sergei Gryanzov Dean W. Felsher |
| author_sort | Renumathy Dhanasekaran |
| collection | DOAJ |
| description | The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Quantitative image analysis of MRI was used to demonstrate the inhibition of HCC and RCC progression. After 4 weeks of drug treatment, tumors had regressed histologically. ASOs depleted MYC mRNA and protein expression in primary tumors in vivo, as demonstrated by real-time PCR and immunohistochemistry. Treatment with MYC ASO in vivo, but not with a control ASO, decreased proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruitment of CD4+ T cells. Importantly, although MYC ASO reduced both mouse Myc and transgenic human MYC, the ASO was not associated with significant toxicity. Lastly, we demonstrate that MYC ASO inhibits the growth of human liver cancer xenografts in vivo. Our results illustrate that targeting MYC expression in vivo using ASO can suppress tumorigenesis by phenotypically eliciting both tumor-intrinsic and microenvironment hallmarks of oncogene addiction. Hence, MYC ASO therapy is a promising strategy to treat MYC-driven human cancers. |
| first_indexed | 2024-12-13T16:05:58Z |
| format | Article |
| id | doaj.art-bc11f22a57154389bb3c27396566ada8 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-13T16:05:58Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-bc11f22a57154389bb3c27396566ada82022-12-21T23:39:03ZengElsevierMolecular Therapy: Nucleic Acids2162-25312020-09-0121850859MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCCRenumathy Dhanasekaran0Jangho Park1Alekesey Yevtodiyenko2David I. Bellovin3Stacey J. Adam4Anand Rajan KD5Meital Gabay6Hanan Fernando7Julia Arzeno8Vinodhini Arjunan9Sergei Gryanzov10Dean W. Felsher11Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADepartment of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA;Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USADivision of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USAMaia Biotechnology Inc, Chicago, IL, USADivision of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA; Corresponding author: Dean W. Felsher, Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA.The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Quantitative image analysis of MRI was used to demonstrate the inhibition of HCC and RCC progression. After 4 weeks of drug treatment, tumors had regressed histologically. ASOs depleted MYC mRNA and protein expression in primary tumors in vivo, as demonstrated by real-time PCR and immunohistochemistry. Treatment with MYC ASO in vivo, but not with a control ASO, decreased proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruitment of CD4+ T cells. Importantly, although MYC ASO reduced both mouse Myc and transgenic human MYC, the ASO was not associated with significant toxicity. Lastly, we demonstrate that MYC ASO inhibits the growth of human liver cancer xenografts in vivo. Our results illustrate that targeting MYC expression in vivo using ASO can suppress tumorigenesis by phenotypically eliciting both tumor-intrinsic and microenvironment hallmarks of oncogene addiction. Hence, MYC ASO therapy is a promising strategy to treat MYC-driven human cancers.http://www.sciencedirect.com/science/article/pii/S2162253120301979MYC oncogeneantisense oligonucleotidehepatocellular carcinomarenal cell carcinomatargeted therapy |
| spellingShingle | Renumathy Dhanasekaran Jangho Park Alekesey Yevtodiyenko David I. Bellovin Stacey J. Adam Anand Rajan KD Meital Gabay Hanan Fernando Julia Arzeno Vinodhini Arjunan Sergei Gryanzov Dean W. Felsher MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC Molecular Therapy: Nucleic Acids MYC oncogene antisense oligonucleotide hepatocellular carcinoma renal cell carcinoma targeted therapy |
| title | MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC |
| title_full | MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC |
| title_fullStr | MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC |
| title_full_unstemmed | MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC |
| title_short | MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC |
| title_sort | myc aso impedes tumorigenesis and elicits oncogene addiction in autochthonous transgenic mouse models of hcc and rcc |
| topic | MYC oncogene antisense oligonucleotide hepatocellular carcinoma renal cell carcinoma targeted therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2162253120301979 |
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