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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

Creating novel mouse models of lung cancer

Mouse Models

Squamous cell carcinoma (SCC) of the lung is a subtype of NSCLC that leads to ~40,000 deaths each year in the US alone. Whereas numerous mouse models of adenocarcinoma have been created and used to study the underlying biology and treatment of adenocarcinoma, relatively less is known about SCC. In 2011, The Cancer Genome Atlas (TCGA) sequenced human squamous lung tumors and identified the most frequently altered genes. Sox2 is one of the most frequently altered genes in human SCC, amplified in ~21% and overexpressed in 60-90% of tumors. We used a lentiviral approach to deliver candidate squamous-associated oncogenes to the mouse lung 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).

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 frequently co-occurs with Sox2 expression in human SCC. Mouse SCCs highly resemble their human counterparts at the level of histopathology, biomarker expression and signaling pathway activation. More recently, we have improved our mouse models by decreasing the latency of tumor development by altering additional genes involved in human squamous lung cancer. Sox2/Lkb1/Nkx2-1mice develop squamous tumors in 3–4 months that highly resemble the human disease (Mollaoglu et al., Immunity, 2018). We found that squamous tumors have an enrichment of neutrophils with features that suggest the neutrophils promote squamous lung cancer. We are using these models to identify:

  1. How the cell of origin impacts SCC development
  2. Cooperating genetic events associated with SCC
  3. Therapeutic targets for SCC
  4. Therapeutic vulnerabilities in the immune microenvironment
  5. The function of neutrophils in SCC

Identifying drug resistance mechanisms in different subtypes of lung cancer

Lung ModelTumors

Small cell lung cancer (SCLC) represents ~15% of all lung cancer cases. SCLC is a neuroendocrine lung tumor that is highly aggressive with high rates of metastases and acquired chemotherapy resistance. The average survival time of patients with SCLC is only 10 months, and treatment options have remained unchanged for almost 40 years. Mouse models of SCLC have been created based on conditional genetic loss of the tumor suppressor genes Rb1and p53, which are both lost in the vast majority of SCLCs. Amplification and overexpression of MYC family genes, including C-MYC, L-MYC, and N-MYC, are also common in SCLC. By combining Myc overexpression with Rb1 and p53 loss, we developed a new genetically-engineered mouse model that recapitulates a specific subtype of human SCLC (Mollaoglu et al, Cancer Cell, 2017). Tumors in these mice develop rapidly, as early as 5 weeks, are highly metastatic, and are sensitive to combined treatment with an Aurora Kinase inhibitor and chemotherapy. Using gene expression analysis, we found distinct molecular profiles associated with human and mouse SCLC tumors with high MYC levels. More recently, we have used unbiased approaches to better understand how MYC-high SCLC is distinct from MYC-low SCLC. Using metabolite profiling, we found that MYC-high SCLC is metabolically distinct and highly dependent on arginine for survival (Chalishazar et al., Clin Can Res, 2019). We are actively working with numerous clinicians to translate these findings to clinical trials.

Our work seeks to identify new therapeutic targets for SCLC using single-cell sequencing technologies, drug screening, and comparative analyses between mouse and human. Understanding how the genetic characteristics of a given tumor dictate therapeutic response will help tailor therapy to the individual.

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. We previously described a novel pathway that may contribute to wildtype p53-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. Although not a current area of focus, 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.

Caspase

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. Dammert MA, Brägelmann J, Olsen RR, Böhm S, Monhasery N, Whitney CP, Chalishazar MD, Tumbrink HL, Guthrie MR, Klein S, Ireland AS, Ryan J, Schmitt A, Marx A, Ozretić L, Castiglione R, Lorenz C, Jachimowicz RD, Wolf E, Thomas RK, Poirier JT, Büttner R, Sen T, Byers LA, Reinhardt HC, Letai A, Oliver TG, Sos ML. MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat Commun2019 Aug 2;10(1):3485doi: 10.1038/s41467-019-11371-x. PubMed PMID: 31375684.

  2. Chalishazar MD, Wait SJ, Huang F, Ireland AS, Mukhopadhyay A, Lee Y, Schuman S, Guthrie MR, Berrett K, Vahrenkamp J, Hu Z, Kudla M, Modzelewska K, Wang G, Ingolia NT, Gertz J, Lum DH, Cosulich SC, Bomalaski JS, DeBerardinis RJ, Oliver TG. MYC-driven small cell lung cancer is metabolically distinct and vulnerable to arginine depletion. Clin Cancer Res.2019 Jun 4;doi: 10.1158/1078-0432.CCR-18-4140. [Epub ahead of print] PubMed PMID: 31164374; NIHMSID:NIHMS1531181.

  3. Guo B, Oliver TG. Partners in Crime: Neutrophil-CTC Collusion in Metastasis. Trends Immunol2019 May 14;doi: 10.1016/j.it.2019.04.009. [Epub ahead of print] PubMed PMID: 31101536; NIHMSID:NIHMS1037431.

  4. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, Heymach JV, Johnson JE, Lehman JM, MacPherson D, Massion PP, Minna JD, Oliver TG, Quaranta V, Sage J, Thomas RK, Vakoc CR, Gazdar AF. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer2019 May;19(5):289-297doi: 10.1038/s41568-019-0133-9. Review. PubMed PMID: 30926931; PubMed Central PMCID: PMC6538259.

  5. Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Arya R, Camolotto SA, Mosbruger TL, Stubben CJ, Conley CJ, Bhutkar A, Vahrenkamp JM, Berrett KC, Cessna MH, Lane TE, Witt BL, Salama ME, Gertz J, Jones KB, Snyder EL, Oliver TG.The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity2018 Oct 16;49(4):764-779.e9doi: 10.1016/j.immuni.2018.09.020. PubMed PMID: 30332632; PubMed Central PMCID: PMC6197489.

  6. Wagner AH, Devarakonda S, Skidmore ZL, Krysiak K, Ramu A, Trani L, Kunisaki J, Masood A, Waqar SN, Spies NC, Morgensztern D, Waligorski J, Ponce J, Fulton RS, Maggi LB Jr, Weber JD, Watson MA, O'Conor CJ, Ritter JH, Olsen RR, Cheng H, Mukhopadhyay A, Can I, Cessna MH, Oliver TG, Mardis ER, Wilson RK, Griffith M, Griffith OL, Govindan R.Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer. Nat Commun2018 Sep 17;9(1):3787doi: 10.1038/s41467-018-06162-9. PubMed PMID: 30224629; PubMed Central PMCID: PMC6141466.

  7. Huang F, Ni M, Chalishazar MD, Huffman KE, Kim J, Cai L, Shi X, Cai F, Zacharias LG, Ireland AS, Li K, Gu W, Kaushik AK, Liu X, Gazdar AF, Oliver TG, Minna JD, Hu Z, DeBerardinis RJ. Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers. Cell Metab. 2018 Sep 4;28(3):369-382.e5. doi: 10.1016/j.cmet.2018.06.005. Epub 2018 Jun 28. PubMed PMID: 30043754; PubMed Central PMCID: PMC6125205.

  8. Zhang W, Girard L, Zhang YA, Haruki T, Papari-Zareei M, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res. 2018 Feb;7(1):32-49. PubMed PMID: 29535911; PubMed Central PMCID: PMC5835590.

  9. Cardnell RJ, Li L, Sen T, Bara R, Tong P, et al. Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget. 2017 Sep 26;8(43):73419-73432. PubMed PMID: 29088717; PubMed Central PMCID: PMC5650272.

  10. Brägelmann J, Böhm S, Guthrie MR, Mollaoglu G, Oliver TG, et al. Family matters: How MYC family oncogenes impact small cell lung cancer. Cell Cycle. 2017 Aug 18;16(16):1489-1498. PubMed PMID: 28737478; PubMed Central PMCID: PMC5584863.

  11. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, et al. MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell. 2017 Feb 13;31(2):270-285. PubMed PMID: 28089889; NIHMSID: NIHMS838387; PubMed Central PMCID: PMC5310991.

  12. Terry MR, Arya R, Mukhopadhyay A, Berrett KC, Clair PM, et al. Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo. Cell Death Differ. 2015 May;22(5):719-30. PubMed PMID: 25301067; PubMed Central PMCID: PMC4392070.

  13. Mukhopadhyay A, Oliver TG. Mighty mouse breakthroughs: a Sox2-driven model for squamous cell lung cancer. Mol Cell Oncol. 2015 Apr-Jun;2(2):e969651. PubMed PMID: 27308419; PubMed Central PMCID: PMC4904963.

  14. Oliver TG, Patel J, Akerley W. Squamous non-small cell lung cancer as a distinct clinical entity. Am J Clin Oncol. 2015 Apr;38(2):220-6. PubMed PMID: 25806712.

  15. Masin M, Vazquez J, Rossi S, Groeneveld S, Samson N, et al. GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer. Cancer Metab. 2014;2:11. PubMed PMID: 25097756; PubMed Central PMCID: PMC4122054.

  16. Mukhopadhyay A, Berrett KC, Kc U, Clair PM, Pop SM, et al. Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep. 2014 Jul 10;8(1):40-9. PubMed PMID: 24953650; NIHMSID: NIHMS680248; PubMed Central PMCID: PMC4410849.

  17. Curry NL, Mino-Kenudson M, Oliver TG, Yilmaz OH, Yilmaz VO, et al. Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction. Cancer Discov. 2013 Aug;3(8):908-21. PubMed PMID: 23719831; NIHMSID: NIHMS486814; PubMed Central PMCID: PMC3743121.

  18. Xue W, Meylan E, Oliver TG, Feldser DM, Winslow MM, et al. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov. 2011 Aug;1(3):236-47. PubMed PMID: 21874163; NIHMSID: NIHMS315465; PubMed Central PMCID: PMC3160630.

  19. Oliver TG, Meylan E, Chang GP, Xue W, Burke JR, et al. Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell. 2011 Jul 8;43(1):57-71. PubMed PMID: 21726810; NIHMSID: NIHMS312217; PubMed Central PMCID: PMC3160283.

  20. Doles J, Oliver TG, Cameron ER, Hsu G, Jacks T, et al. Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy. Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20786-91. PubMed PMID: 21068376; PubMed Central PMCID: PMC2996428.

  21. Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, et al. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev. 2010 Apr 15;24(8):837-52. PubMed PMID: 20395368; PubMed Central PMCID: PMC2854397.

  22. Cowley DO, Rivera-Pérez JA, Schliekelman M, He YJ, Oliver TG, et al. Aurora-A kinase is essential for bipolar spindle formation and early development. Mol Cell Biol. 2009 Feb;29(4):1059-71. PubMed PMID: 19075002; PubMed Central PMCID: PMC2643803.

  23. Schliekelman M, Cowley DO, O'Quinn R, Oliver TG, Lu L, et al. Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. Cancer Res. 2009 Jan 1;69(1):45-54. PubMed PMID: 19117986; NIHMSID: NIHMS761127; PubMed Central PMCID: PMC4770788.

  24. Fogarty MP, Emmenegger BA, Grasfeder LL, Oliver TG, Wechsler-Reya RJ. Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2973-8. PubMed PMID: 17299056; PubMed Central PMCID: PMC1815291.

  25. Oliver TG, Read TA, Kessler JD, Mehmeti A, Wells JF, et al. Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development. 2005 May;132(10):2425-39. PubMed PMID: 15843415.

  26. Oliver TG, Wechsler-Reya RJ. Getting at the root and stem of brain tumors. Neuron. 2004 Jun 24;42(6):885-8. PubMed PMID: 15207233.

  27. Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7331-6. PubMed PMID: 12777630; PubMed Central PMCID: PMC165875.

     

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Last Updated: 8/7/19