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Trudy G. Oliver

Associate Professor of Oncological Sciences

oliver

B.S. Oklahoma Baptist University

Ph.D. Duke University

Research

References

trudy.oliver@hci.utah.edu

Trudy Oliver's Lab Page

Trudy Oliver's PubMed Literature Search

Molecular Biology Program

Lung Cancer, Drug Resistance, Mouse Models, Developmental Signaling Pathways, Tumor Progression, Metabolism, Immunology, Transcription Factors

Research

A novel mouse model of squamous cell lung cancer
Squamous cell carcinoma (SCC) of the lung is a common subtype of lung cancer that leads to ~40,000 deaths each year in the US alone. Whereas numerous mouse models of other lung tumor subtypes have been created and used to study their underlying biology and treatment, relatively less is known about SCC. In 2012, The Cancer Genome Atlas (TCGA) sequenced ~200 human squamous lung tumors and identified the most frequently altered genes. Our lab seeks to alter these genes in vivo to test their role in tumor initiation and progression. Because mice can inhale viruses, our lab uses lentiviral technology to deliver genes specifically to the mouse lung. To create two genetic “hits,” we used lentiviruses to deliver candidate squamous-associated oncogenes along with Cre recombinase, which allows for conditional deletion of tumor suppressor genes. We discovered that Sox2 expression cooperates with loss of the tumor suppressor Lkb1 to promote SCC (Mukhopadhyay et al, Cell Reports, 2014). This model represents the first Sox2-driven mouse model of SCC. Sox2 is one of the most frequently altered genes in human SCC, amplified in ~21% and overexpressed in 60-90% of tumors.

Mouse

Lkb1 is altered in 6-19% of human SCCs and its loss is associated with activation of the mTOR pathway. We observed that mTOR pathway activity co-occurs with Sox2 expression in over half of human SCCs. Mouse SCCs highly resemble their human counterparts at the level of histopathology, biomarker expression and signaling pathway activation (Figure 1).

We are using this novel mouse model to identify:

  1. the cell of origin of SCC
  2. cooperating genetic events associated with SCC using CRISPR technology
  3. novel therapeutic targets for SCC

Identifying drug resistance mechanisms in different subtypes of lung cancer
Our lab seeks to identify mechanisms of drug resistance in lung cancer. Small cell lung cancer (SCLC) is initially highly responsive to chemotherapy but frequently acquires vicious resistance. SCLC has been treated with chemotherapy for over 40 years, and there are still no targeted therapies approved for SCLC treatment.

The tumor cell of origin and/or underlying genetic lesions may play a critical role in determining chemotherapy response. Mouse models of SCLC have been created based on conditional genetic loss of the tumor suppressors Rb and p53, which are both lost in virtually all SCLCs. Our lab uses genomic and gene expression analyses to identify and compare chemotherapy resistance mechanisms in mouse models of SCLC. Understanding how the genetic characteristics of a given tumor dictate therapeutic response will help tailor therapy to the individual. Our lab is also using CRISPR technology to study the function of genes altered in SCLC in vivo, as well as creating novel genetically engineered mouse models of SCLC.

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Regulation of the Mdm2/p53 tumor suppressor network in lung cancer
The tumor suppressor p53 is the most commonly mutated gene in human cancer. Approximately 50% of tumors harbor point mutations in p53, but virtually all tumors have a defect in the p53 pathway. As a transcription factor, p53 responds to cellular stress by inducing target genes that promote cell cycle arrest, DNA repair, apoptosis or senescence. Because p53 plays a central role in determining cell fate decisions between life and death, elucidating the signaling circuitry that governs p53 function is critical for understanding tumorigenesis and manipulating p53 for therapeutic purposes.

The role of p53 in chemotherapy response is controversial. In some tissues, p53 promotes apoptosis, which would promote tumor cell death. In other tissues, p53 can promote cell cycle arrest, DNA damage repair and senescence—processes that would protect tumors from chemotherapy. Recently, it has become appreciated that in breast, bladder and lung cancer, wildtype p53 can promote chemotherapy resistance. Our recent findings have uncovered a novel pathway that we hypothesize helps wildtype p53 promote-mediated chemotherapy resistance. We discovered that the Caspase-2-PIDDosome complex is responsible for cleavage and inhibition of Mdm2, a master regulator of p53. Cleavage of Mdm2 converts it from an inhibitor of p53 to an activator of p53 (Figure 3). One of our lab goals is to determine the role of Mdm2 cleavage in p53 signaling and therapeutic resistance. These studies will contribute to our understanding of drug resistance mechanisms as well as p53 pathway regulation in normal development and cancer.

Oliver Figure

The Caspase-2-PIDDosome promotes p53 stability and activity. PIDD is a p53 target gene that is induced upon DNA damage. PIDD accumulation promotes assembly of the Caspase-2-PIDDosome complex, which activates the protease Caspase-2. Caspase-2 cleaves and removes the RING domain of Mdm2, converting Mdm2 from an inhibitor of p53 to an activator of p53 (Oliver et al, Mol Cell, 2011).

References

  1. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG (2017). MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell. Feb 13;31(2):270-285.
  2. Brägelmann J, Böhm S, Guthrie MR, Mollaoglu G, Oliver TG, Sos ML (2017) Family matters: how MYC family oncogenes impact small cell lung cancer. Cell Cycle. Jul 24:0.
  3. Terry MR, Arya R, Mukhopadhyay A, Berrett KC, Clair PM, Witt B, Salama ME, Bhutkar A, Oliver TG (2015). Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo. Cell Death Differ. Apr;22(5):719-30.
  4. Mukhopadhyay A, Oliver TG (2014). Mighty mouse breakthroughs: a Sox2-driven model for squamous cell lung cancer. [Review]. Molecular and Cellular Oncology. Nov 11;2(2):e969651.
  5. Mukhopadhyay A, Berrett KC, Kc U, Clair PM, Pop SM, Carr SR, Witt BL, Oliver TG (2014). Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep, Jul 10;8(1):40-9.
  6. Oliver TG, Patel J, Akerley W (2015). Squamous Non-small Cell Lung Cancer as a Distinct Clinical Entity. Am J Clin Oncol, Apr;38(2):220-6.
  7. Curry NL, Mino-Kenudson M, Oliver TG, Yilmaz OH, Yilmaz VO, Moon JY, Jacks T, Sabatini DM, Kalaany NY (2013). Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction. Cancer Discov. Aug;3(8):908-21.
  8. Xue W, Meylan E, Oliver TG, Feldser DM, Winslow MM, Bronson R, Jacks T (2011). Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov. Aug;1(3):236-47.
  9. Oliver TG, Meylan E, Chang GP, Xue W, Burke JR, Humpton TJ, Hubbard D, Bhutkar A, Jacks T (2011). Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell. Jul 8;43(1):57-71.
  10. Doles J, Oliver TG, Cameron ER, Hsu G, Jacks T, Walker GC, Hemann MT (2010). Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy. Proc Natl Acad Sci USA. Nov 30;107(48):20786-91.
  11. Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, Cheng MH, Subramanian A, Mu D, Powers S, Crowley D, Bronson RT, Whittaker CA, Bhutkar A, Lippard SJ, Golub T, Thomale J, Jacks T, Sweet-Cordero EA (2010). Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev. Apr 15;24(8):837-52.
  12. Cowley DO, Rivera-Pérez JA, Schliekelman M, He YJ, Oliver TG, Lu L, O'Quinn R, Salmon ED, Magnuson T, Van Dyke T (2009). Aurora-A kinase is essential for bipolar spindle formation and early development. Mol Cell Biol. Feb;29(4):1059-71.
  13. Schliekelman M, Cowley DO, O'Quinn R, Oliver TG, Lu L, Salmon ED, Van Dyke T (2009). Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. Cancer Res. Jan 1;69(1):45-54.
  14. Fogarty MP, Emmenegger BA, Grasfeder LL, Oliver TG, Wechsler-Reya RJ (2007). Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. Proc Natl Acad Sci USA. Feb 20;104(8):2973-8.
  15. Oliver TG, Read TA, Kessler JD, Mehmeti A, Wells JF, Huynh TT, Lin SM, Wechsler-Reya RJ (2005). Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development. May;132(10):2425-39.
  16. Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, Wickramasinghe R, Scott MP, Wechsler-Reya RJ (2003). Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA. Jun 10;100(12):7331-6.

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Last Updated: 7/26/17