Sheri Holmen

Professor of Surgery and
Adjunct Associate Professor of Oncological Sciences

Holmen

B.S. Western Michigan University

Ph.D. Mayo Clinic College of Medicine

Research

References

Sheri.Holmen@hci.utah.edu

Sheri Holmen's Lab Page

Sheri Holmen's PubMed Literature Search

 

Molecular Biology Program

Tumor Initiation and Progression

Research

Our lab studies the roles of different genes in tumor initiation and progression In order to define critical targets in cancer cells that can become the focus for therapeutic intervention. We have concentrated our initial efforts on using a reverse genetic approach in tumors that are refractory to conventional therapies including metastatic melanoma and glioblastoma. We use a series of replication-competent retroviral vectors based on Rous sarcoma virus (RSV), a member of the avian leukosis virus (ALV) family. RSV is the only known naturally occurring, replication-competent retrovirus that carries an oncogene, src. In the RCAS viral vectors, the region encoding src (which is dispensable for viral replication) has been replaced by a gateway cassette. Foreign genes inserted into this region are expressed from the viral LTR promoter via a subgenomic splice site (just as src is in RSV). The ability of this vector to infect non-avian cells relies on expression of the corresponding receptor, TVA, on the cell surface. The TVA receptor is typically introduced into mammalian cells (or mice) via an inducible and/or tissue-specific promoter. Therefore, this system allows for tissue- and cell-specific targeted infection of mammalian cells through ectopic expression of the viral receptor.

Melanoma
A major initiative in our research program has been to develop a novel high-throughput mouse model of melanoma based on retroviral-mediated gene delivery to postnatal melanocytes. We have successfully developed this model and further employed the use of this model to better understand melanoma biology and response to therapy. We have identified genes and proteins with differential roles in melanoma initiation and progression as well as intrinsic resistance to mitogen-activated protein kinase (MAPK) inhibition. Our group has also extended the utility of this mouse model system by engineering the viruses to be responsive to doxycycline in the presence of Tet-off or Tet-on proteins. This allows us to regulate the expression of the delivered genes post-infection in vivo, define the role of specific genes in tumor maintenance, and develop models of resistance. We hope to use these tools to design rational combination therapies to improve outcome in patients with advanced melanoma.

Glioma
Recently, high-throughput efforts such as The Cancer Genome Atlas (TCGA) pilot project and extensive sequencing projects have yielded novel genetic information about gliomas. Our laboratory utilizes a robust glioma mouse model based on the RCAS/TVA system, which was originally pioneered by Dr. Harold Varmus and Dr. Eric Holland. In this model, the retroviral receptor TVA is expressed under the control of the Nestin promoter, which is active in neural and glial progenitors.This mouse model allows efficient and cost-effective modeling of gliomas because testing of a new gene simply requires generating a new retroviral vector not a new transgenic mouse. Because a new virus can be made and evaluated quickly (<4 weeks) in comparison to the time required to make a new transgenic mouse, we were able to quickly demonstrate a role for BRAFV600E in the etiology of this disease. In addition, multiple genetic alterations can be introduced into the same animal without the cost associated with mating multiple strains of transgenic or knockout mice allowing us to assess cooperating events. We plan to use this model to validate the genes identified by the TCGA study and identify rational targets for therapy.

References

  1. Ray A, Williams MA, Meek SM, Bowen RC, Grossmann KF, Andtbacka RH, Bowles TL, Hyngstrom JR, Leachman SA, Grossman D, Bowen GM, Holmen SL, VanBrocklin MW, Suneja G, Khong HT (2016). A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma. Oncotarget, Jul 6, doi:10.18632/oncotarget.10453
  2. Kircher DA, Arave RA, Cho JH, Holmen SL (2016). Melanoma metastases caught in the AKT. Mol Cell Oncol, 3(2), e1128516.
  3. Cho JH, Robinson JP, Arave RA, Burnett WJ, Kircher DA, Chen G, Davies MA, Grossmann AH, VanBrocklin MW, McMahon M, Holmen SL (2015). AKT1 Activation Promotes Development of Melanoma Metastases. Cell Rep, 13(5), 898-905.
  4. Shin CH, Grossmann AH, Holmen SL, Robinson JP (2015). The BRAF kinase domain promotes the development of gliomas in vivo. Genes Cancer, 6(1-2), 9-18.
  5. Joshi S, Wels C, Beham-Schmid C, Fukunaga-Kalabis M, Holmen SL, Otte M, Herlyn M, Waldhoer M, Schaider H (2015). Gα13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma. Int J Cancer, 137(6), 1503-8.
  6. Robinson GL, Robinson JP, Lastwika KJ, Holmen SL, Vanbrocklin MW (2013). Akt signaling accelerates tumor recurrence following ras inhibition in the context of ink4a/arf loss. Genes Cancer, 4(11-12), 476-85.
  7. Rokstad IS, Rokstad KS, Holmen S, Lehmann S, Assmus J (2013). Electronic optional guidelines as a tool to improve the process of referring patients to specialized care: an intervention study. Scand J Prim Health Care, 31(3), 166-71.
  8. Cohen AL, Holmen SL, Colman H (2013). IDH1 and IDH2 mutations in gliomas. [Review]. Curr Neurol Neurosci Rep, 13(5), 345.
  9. Robinson GL, Robinson JP, Lastwika KJ, Holmen SL, Vanbrocklin MW (2013). Akt signaling accelerates tumor recurrence following ras inhibition in the context of ink4a/arf loss. Genes Cancer, 4(11-12), 476-85.
  10. Merlino G, Flaherty K, Acquavella N, Day CP, Aplin A, Holmen S, Topalian S, Van Dyke T, Herlyn M (2013). Meeting report: The future of preclinical mouse models in melanoma treatment is now. Pigment Cell Melanoma Res, 26(4), E8-E14.
  11. Vanbrocklin MW, Robinson JP, Lastwika KJ, McKinney AJ, Gach HM, Holmen SL (2012). Ink4a/Arf loss promotes tumor recurrence following Ras inhibition. Neuro Oncol, 14(1), 34-42.

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Last Updated: 8/4/17