GutPangea.jpg

Birth, Life, and Death of Intestinal cells

What we study

 

Our work utilizes the fascinating characteristics of intestinal stem cells to address fundamental questions in cell and cancer biology: How do cells identify, measure, and respond to each other and to their environment? What are the signals that control the renewal and regeneration of tissues? How do these signals go wrong in cancer? Our long-term goal is to uncover an underlying circuit theory behind these behaviors – a set of predictive principles that tell us how complex functionality arises from simpler biological components. We have a particular interest in kinase networks that regulate healthy tissue homeostasis and become damaged in cancer. Through our quantitative high-throughput imaging and drug discovery efforts, we are finding new ways to understand and repair these networks.

Projects

 

 
Kinome-Functional.jpg

1. Phenomics of the human kinome in colonic stem cells.

Understanding the relationship of genotype to phenotype is fundamental to comprehending living systems. This is a complex problem because phenotype is not simply one parameter of a system but hundreds, if not thousands, of parameters connected to one another in unclear ways. Thus a high-dimensional characterization is needed in studying gene function. The human kinome is highly studied, but most commonly in a one-gene-one-phenotype style. The goal of this project is to create a rich (high-dimensional) phenotypic description of each kinase in colonic stem cells and then to organize the entire kinome into groupings of similar function. We are validating functional groups through mechanistic studies in 2 and 3-D intestinal cell culture. This work will characterize kinase function in the intestinal epithelium and uncover new signals controlling tissue homeostasis.

2: GSK-3 signaling in crypt maintenance and drug resistance.

Evidence suggests the protein kinase, GSK-3, is highly regulated in the intestinal stem cell niche in vivo. Additionally, our studies have shown decreased GSK-3 activity stimulates stem cell maintenance and provides significant drug resistance. To understand the role of GSK-3 activity in intestinal crypt homeostasis and drug response, we are developing a single cell live reporter for GSK-3 activity. Using time-lapse microscopy, we are exploring the dynamics of GSK-3 activity in the maintenance of the stem cell niche and identifing microenvironmental signals that regulate GSK-3 and produce drug resistance. The goal is to uncover molecular mechanisms by which epithelia self-organize and evade cytotoxic drugs.

Drug-screen.jpg

3: Discovery and characterization of small molecule kinase activators.

Small molecule inhibition of kinase activity is well established as a fruitful therapeutic strategy. Yet, widely neglected is the development of small molecule kinase activators for rationally selected targets. GSK-3 is an outstanding candidate for small molecule activation due to its many allosteric pockets and its inactivation in various disease states. We are conducting a two-step (enzymatic followed by cell-based imaging) high throughput screen of >250,000 compounds to identify small molecule activators of GSK-3. Utilizing a novel high-dimensional structure-activity relationship (HD-SAR) approach, we are categorizing the compounds into three major classes: 1) proliferation, 2) metabolism, and 3) cytoskeleton. These compounds will be valuable both as tools for biologists and as potential lead compounds for cancer drug development.

 

Eye Candy

A few videos of experimentation, simulation and automation of enteroids

 
 
 

PEOPLE

 
 
1 (2).jpg

Curtis Thorne

Assistant Professor of Cellular and Molecular Medicine and the UA Cancer Center.

Curtis received his B.S. in 2000 from Baylor University where he concentrated in Biology and Chemistry. He was then a technician for 2 years at Baylor College of Medicine in the laboratory of Dr. Adrian Lee studying growth factor signaling in breast cancer. Curtis received his Ph.D. in 2010 from Vanderbilt University in Cell and Developmental Biology under Dr. Ethan Lee. In graduate school he discovered a novel therapeutic for the treatment of colon cancer. He then conducted postdoctoral studies as an American Cancer Society Fellow at University of Texas Southwestern in the laboratories of Dr. Steven Altschuler and Dr. Lani Wu (now at UCSF). There he developed a high throughput method for culturing intestinal stem cells combined with automated cell imaging. Using these approaches he discovered novel drug combinations for the treatment colon cancer. While at UT Southwestern, Curtis received a NIH Pathway to Independence Award with additional training in kinase biochemistry in the lab of Dr. Melanie Cobb.

In 2017, Curtis took a position as Assistant Professor in the Department of Cellular and Molecular Medicine at the University of Arizona. He is also a member of the University of Arizona Cancer Center.

Email: curtisthorne@email.arizona.edu

 
IMG_3604.JPG

Matthew Estremera

Matthew received his B.S. in 2017 from the University of Arizona where he studied Molecular and Cellular Biology. During his time, he interned in the lab of Dr. Lisa Nagy where he focused on Tribolium castaneum segmentation and development. The balance of logic and creativity inspire Matthew to pursue research and investigation. In his free time he plays ultimate Frisbee and enjoys the outdoors.

 

Lab Alumni

image1.jpeg

Sofia De La Cruz

Sofia is currently at Kenyon College.

 

Opportunities

Graduate students

We have multiple opportunities for Ph.D. students to train in the Thorne Lab. If you are interested in our research, email Dr. Thorne or drop by and chat!

Postdoctoral applicants

We are always looking for talented and enthusiastic postdocs with strong training as experimentalists or theorists. Candidates with any combination of skills in organoid culture, biochemistry, drug discovery, machine learning, signal processing, or mathematical modeling are encouraged to contact Dr. Thorne.

 

Check out why we think Tucson and U of A are great places to do science.

 

 

Publications

 

 

2017

Coster, A. D., C. A. Thorne, L. F. Wu, and S. J. Altschuler, "Examining Crosstalk among Transforming Growth Factor β, Bone Morphogenetic Protein, and Wnt Pathways.", J Biol Chem, vol. 292, issue 1, pp. 244-250, 2017 Jan 06. PMCID: PMC5217683  PMID: 27895117

Coate, K. C., G. Hernandez, C. A. Thorne, S. Sun, T. D. V. Le, K. Vale, S. A. Kliewer, and D. J. Mangelsdorf, "FGF21 Is an Exocrine Pancreas Secretagogue.", Cell Metab, vol. 25, issue 2, pp. 472-480, 2017 Feb 07. PMCID: PMC5299054  PMID: 28089565

Li, B., D. Orton, L. R. Neitzel, L. Astudillo, C. Shen, J. Long, X. Chen, K. C. Kirkbride, T. Doundoulakis, M. L. Guerra,  J. Zaias, D. L. Fei, J. Rodriguez-Blanco, C. Thorne, Z. Wang, K. Jin, D. M. Nguyen, L. R. Sands, F. Marchetti, M. T. Abreu, M. H. Cobb, A. J. Capobianco, E. Lee, D. J. Robbins, "Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.", Sci Signal, vol. 10, issue 485, 2017 Jun 27. PMID: 28655862

2016

Wang, Z., O. Tacchelly-Benites, E. Yang, C. A. Thorne, H. Nojima, E. Lee, and Y. Ahmed, "Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase.", Genetics, vol. 203, issue 1, pp. 269-81, 2016 05. PMCID: PMC4858779  PMID: 26975665

2015

Thorne, C. A., C. Wichaidit, A. D. Coster, B. A. Posner, L. F. Wu, and S. J. Altschuler, "GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors.", Nat Chem Biol, vol. 11, issue 1, pp. 58-63, 2015 Jan. PMCID: PMC4270937  PMID: 25402767

Karra, A. S., C. A. Taylor, C. A. Thorne, and M. H. Cobb, "A Kinase Divided.", Cancer Cell, vol. 28, issue 2, pp. 145-7, 2015 Aug 10.PMID: 26267529

2013

Saito-Diaz, K., T. W. Chen, X. Wang, C. A. Thorne, H. A. Wallace, A. Page-McCaw, and E. Lee, "The way Wnt works: components and mechanism.", Growth Factors, vol. 31, issue 1, pp. 1-31, 2013 Feb. PMCID: PMC3697919  PMID: 23256519

Hao, J., A. Ao, L. Zhou, C. K. Murphy, A. Y. Frist, J. J. Keel, C. A. Thorne, K. Kim, E. Lee, and C. C. Hong, "Selective small molecule targeting β-catenin function discovered by in vivo chemical genetic screen.", Cell Rep, vol. 4, issue 5, pp. 898-904, 2013 Sep 12.PMCID: PMC3923627  PMID: 24012757

2012

Hang, B. I., C. A. Thorne, D. J. Robbins, S. S. Huppert, L. A. Lee, and E. Lee, "Screening for small molecule inhibitors of embryonic pathways: sometimes you gotta crack a few eggs.", Bioorg Med Chem, vol. 20, issue 6, pp. 1869-77, 2012 Mar 15. PMCID: PMC3298638  PMID: 22261025

2011

Thorne, C. A., B. LaFleur, M. Lewis, A. J. Hanson, K. K. Jernigan, D. C. Weaver, K. A. Huppert, T. W. Chen, C. Wichaidit, C. S. Cselenyi, et al., "A biochemical screen for identification of small-molecule regulators of the Wnt pathway using Xenopus egg extracts.", J Biomol Screen, vol. 16, issue 9, pp. 995-1006, 2011 Oct. PMCID: PMC3694444  PMID: 21859680

Ni, T. T., E. J. Rellinger, A. Mukherjee, S. Xie, L. Stephens, C. A. Thorne, K. Kim, J. Hu, E. Lee, L. Marnett, et al., "Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling.", Chem Biol, vol. 18, issue 12, pp. 1658-68, 2011 Dec 23. PMCID: PMC3645312  PMID: 22195568

2010

Jernigan, K. K., C. S. Cselenyi, C. A. Thorne, A. J. Hanson, E. Tahinci, N. Hajicek, W. M. Oldham, L. A. Lee, H. E. Hamm, J. R. Hepler, et al., "Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.", Sci Signal, vol. 3, issue 121, pp. ra37, 2010 May 11. PMCID: PMC3088111  PMID: 20460648

Thorne, C. A., A. J. Hanson, J. Schneider, E. Tahinci, D. Orton, C. S. Cselenyi, K. K. Jernigan, K. C. Meyers, B. I. Hang, A. G. Waterson, et al., "Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.", Nat Chem Biol, vol. 6, issue 11, pp. 829-36, 2010 Nov. PMCID: PMC3681608  PMID: 20890287

Alfaro, M. P., A. Vincent, S. Saraswati, C. A. Thorne, C. C. Hong, E. Lee, and P. P. Young, "sFRP2 suppression of bone morphogenic protein (BMP) and Wnt signaling mediates mesenchymal stem cell (MSC) self-renewal promoting engraftment and myocardial repair.", J Biol Chem, vol. 285, issue 46, pp. 35645-53, 2010 Nov 12. PMCID: PMC2975189  PMID: 20826809

Saraswati, S., M. P. Alfaro, C. A. Thorne, J. Atkinson, E. Lee, and P. P. Young, "Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling.", PLoS One, vol. 5, issue 11, pp. e15521, 2010 Nov 29. PMCID: PMC2993965  PMID: 21170416

2008

Cselenyi, C. S., K. K. Jernigan, E. Tahinci, C. A. Thorne, L. A. Lee, and E. Lee, "LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of beta-catenin.", Proc Natl Acad Sci U S A, vol. 105, issue 23, pp. 8032-7, 2008 Jun 10. PMCID: PMC2430354  PMID: 18509060

2007

Tahinci, E., C. A. Thorne, J. L. Franklin, A. Salic, K. M. Christian, L. A. Lee, R. J. Coffey, and E. Lee, "Lrp6 is required for convergent extension during Xenopus gastrulation.", Development, vol. 134, issue 22, pp. 4095-106, 2007 Nov. PMCID: PMC4428168  PMID: 17965054

2003

Thorne, C., and A. V. Lee, "Cross talk between estrogen receptor and IGF signaling in normal mammary gland development and breast cancer.", Breast Dis, vol. 17, pp. 105-14, 2003. PMID: 15687681

 
 
Uofa-looking-NE-crop2.jpg

Contact Info

 

Leon Levy Building,  UA Cancer Center

1515 N. Campbell Ave.

Office: Room 4949B

Office phone: 520-626-0395

Lab: Room 4906

Lab phone: 520-626-3265

Tucson, AZ 85724

 

Name *
Name