Modeling cancer

The initiation and progression of cancer is highly complex.  Thus, a diverse array of animal and cell-based systems is often needed to study different aspects of the disease and different cancer types.  Researchers in MCCB rely on a number of different models for this purpose.  These models include conditional knockout and transgenic mouse lines that allow selective initiation of tumors in distinct cell types to mimic different types of cancer, such as pancreatic and liver cancer.  MCCB researchers studying leukemia also take advantage of “humanized” mice, which allow transplantation of human leukemia cells into mice with a humanized immune system.  Using this unique model to test patient cells, it may be possible to predict factors driving relapse in different patient subpopulations.  Researchers are also utilizing knockout zebrafish lines bearing mutations in genes implicated in cancer-related diseases in humans.  These models allow detailed imaging of cellular defects not possible in mouse models, while also serving as a platform for in vivo small molecule screens for therapeutic agents.

Click on the link below for more details on how cancer and related diseases are being investigated in MCCB labs.

 

Bach Lab

Aberrant activation of gene transcription by the estrogen receptor (ER) plays a crucial role in inducing human breast tumors. Because LIM cofactors RLIM and CLIM regulate the transcriptional activity of ER in breast cancer cells, the Bach lab studies functions of these cofactors in mammary glands and during the formation of breast cancer.

  • Johnsen et al. (2009) Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Res 69, 128-36
  • Jiao et al. (2012) Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells. Cell 149, 630-41
  • Jiao et al. (2013) Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleocytoplasmic shuttling. Mol Biol Cell 24, 3085-96 

Bergmann Lab

Paradoxically, dying cancer cells can be the origin of signals which induce proliferation of surviving cells and thus can cause even stronger tumor growth. The Bergmann Lab has developed genetic models which mimic this process termed “Apoptosis-induced Compensatory Proliferation” (AiP). In genetic screens, they have identified several genes involved in AiP.  The analysis of these genes for understanding the mechanisms of AiP and their potential role in cancer is in progress.

  • Fan Y and Bergmann A (2008). Apoptosis-induced Compensatory Proliferation: The cell is dead. Long live the Cell! Trends in Cell Biology 18, 467-473.
  • Fan Y and Bergmann A (2008). Distinct Mechanisms of Apoptosis-induced Compensatory Proliferation in Proliferating and Differentiating Eye Tissues in Drosophila. Developmental Cell 14, 399-410.
  • Ryoo HD, and Bergmann A (2012). The role of Apoptosis-induced Proliferation for Regeneration and Cancer. In: Cell Survival and Cell Death, Eds: EH Baehrecke, DR Green, S Kornbluth and G Salvesen, Cold Spring Harb Perspect Biol. 4(8). pii: a008797. doi: 10.1101/cshperspect.a008797.
  • Fan Y et al. (2014). Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila. PLoS Genetics 10(1) e1004131. 

Castilla Lab

The Castilla laboratory studies the mechanism of leukemia development using mouse models. To this end, researchers in the Castilla Lab have developed sophisticated mouse models for acute myeloid leukemia to study the mechanisms dictating leukemia development, including conditional knockins.  These are utilized with tissue specific and inducible Cre transgenic mice to better understand the function of driver-mutations in a cell type specific manner. Researchers also utilize and patient derived xenografts to study clonal complexity of patient AML blasts and therapeutic efficacy in vivo. 

  • Kuo et al. (2006) Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell 2006, 9(1):57-68.
  • Pullikan et al. (2012) Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling. Blood, 120(4):868-79.
  • Illendula et al. (2015) Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice.  Science, 347(6223):779-84.

Fazzio Lab

Genes encoding chromatin regulatory proteins encompass some of the most frequent targets of mutation in cancer. However, the contributions of these mutations to oncogenesis are not easily understood, due to the fact that most chromatin regulators regulate expression of thousands of genes, in addition to roles in DNA replication and repair. The Fazzio lab is examining the roles of several chromatin remodeling complexes that have known tumor-suppressive roles, to better understand how their loss leads to cancer.   

Green Lab

The Green lab uses a variety of mouse models that recapitulate many aspects of the genesis, progression and clinical course of human cancers. They have used these mice to perform both directed experiments and functional genomics screens to identify oncogenes and tumor suppressor genes for a variety of malignancies, including breast, lung and brain cancers as well as leukemia.  

  • Sheng et al. (2010) A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.  Nat Med, 16(6):671-7.
  • Lin et al.  (2014) A large-scale RNAi-based mouse tumorigenesis screen identifies new lung cancer tumor suppressors that repress FGFR signaling.  Cancer Discov, 4(10):1168-81.
  • Ma et al.(2014) A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia.Sci Transl Med, 6(252):252ra121.
  • Bhatnagar et al. (2014) TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature, 516(7529):116-20.

Kelliher Lab

Despite advances in the treatment of leukemia, there are populations of patients who still have a poor prognosis, or who relapse and become resistance to standard frontline therapies.  A major focus of the Kelliher lab is to understand the underlying mechanisms that contribute to refractory T cell acute lymphoblastic leukemia (T-ALL).  For this purpose, they utilize the mouse as a model system to understand the genetic and epigenetic basis of therapeutic resistance in T-ALL.   In particular, they rely on genetically engineered mouse models where it is possible to analyze patient-derived xenografts from pediatric and adult T-ALL patients at diagnosis and upon relapse.

  • Knoechel et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet. 46(4):364-70.
  • Roderick et al. (2014) c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood. 123(7):1040-50.

Lewis Lab

Work in the Lewis lab is centered on the characterization of the roles for novel, and established, oncoproteins and tumor suppressors in the genesis and progression of pancreatic and hepatic carcinomas. The lab utilizes a variety of genetically engineered mouse models in these studies. Among other contributions, recent studies have demonstrated a critical role for the insulin-like growth factor receptor in PI3-kinase activation downstream of activated KRAS; the requirement for GLI transcription activation function during pancreatic tumorigenesis; and a novel paracrine WNT signaling mechanism that promotes the development of pancreatic mucinous cystic neoplasms. 

  • Rajurkar et al. (2012) The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. PNAS.  109(17): E1038-47.
  • Appleman et al. (2012) KRASG12D- and BRAFV600E-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling. Mol Cancer Res. 10(9): 1228-39.
  • Sano et al. (2014) Activated Wnt Signaling in Stroma Contributes to Development of Pancreatic Mucinous Cystic Neoplasms. Gastroenterology.146(1): 257-67.

Mao Lab

The Mao laboratory uses genetically modified mouse models to investigate how mis-regulation of the Hedgehog, Hippo and Wnt pathways contribute to initiation, progress, and regulation of tumor microenvironment in gastrointestinal cancers, rhabdomyosarcoma, and uveal melanoma.

  • Rajurkar et al. (2012) The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. PNAS.  109(17): E1038-47.
  • Wang et al. (2013) TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBP function. Molecular Cell 51(2):211-25.
  • Rajurkar et al. (2014) Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis. Oncogene 33(46):5370-8

 

Shaw Lab

The Shaw lab uses both transgenic and orthotopic mouse models to investigate the mechanisms by which carcinoma cells develop more aggressive behavior and acquire the ability to metastasize to secondary organs.  From a translational perspective, the goal of this work is to develop novel targets to predict or to treat metastatic cancer.  The Shaw lab has a longstanding interest in the IGF-1R/insulin signaling pathway, with a focus on the Insulin Receptor Substrate (IRS) proteins and the mechanism by which these essential signaling adaptors regulate tumor progression.  A current focus in the lab is the role of the IRS proteins in cancer stem cells and their contribution to tumor metastasis.

Simin Lab

The Simin lab is interested in genetic pathways that, when perturbed, increase cancer malignancy. The research involves bioinformatics along with molecular and cell biology techniques to engineer cell lines and mouse models that faithfully mimic human cancer evolution. With a greater understanding of the molecular basis of cancer progression we hope to identify potential new treatment avenues.

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