Leight Research Group

In August of 2022, Dr. Leight accepted a teaching focused faculty role in the Department of Biomedical Engineering, and the Leight lab is no longer actively conducting research.

The Leight Lab studied extracellular matrix remodeling in the tumor microenvironment. Specifically, we focused on the development of a fluorescent peptide sensors to measure matrix metalloproteinase (MMP) activity in 3D cellular microenvironments. Read more about our research or check out our publications below!

The Leight lab seeks to understand how the extracellular matrix is remodeled during tumor progression and how this remodeling affects cancer cell function and treatment responsiveness. Towards this goal, we develop new methods and technologies to study the microenvironment. We have focused on two main areas of matrix remodeling, degradation by matrix metalloproteinases (MMPs) and changes in the physical properties of the matrix, such as stiffness and fiber organization.

Matrix metalloproteinase (MMP) expression is elevated in almost all tumor types, including breast, colon, pancreas, and melanoma, and increased expression is often correlated with decreased survival. However, it remains unclear specifically which enzymes (of the 20+ in the MMP family) are important at each stage of disease progression and how proteolysis is regulated in space and time. To investigate MMP activity, we develop new fluorescent biosensors and biomaterials to measure MMP activity in 3D cellular microenvironments. A critical barrier towards achieving this in-depth understanding of the regulation of MMPs is the lack of methods and culture systems to study MMP activity in situ. To overcome this barrier, the Leight lab has developed a unique approach in which 3D hydrogel cell culture platforms are functionalized with MMP fluorogenic substrates to enable measurement and visualization of MMP activity in space and time. We have also developed a new zymographic technique using the MMP fluorogenic substrates, which has given new insight into the specific proteases responsible for hydrogel degradation. Beyond cancer biology, this knowledge will aid in the rational design of resorbable biomaterials for applications such as drug delivery and regenerative medicine.

New studies in the lab are focused on using these fluorescent sensor functionalized hydrogels in other applications. We have developed and characterized a high throughput version of this system, and we are using this system for ex vivo culture of human tumor tissue, with future applications in drug screening and personalized medicine. The fluorogenic sensor can also be visualized using microscopy, and we are developing new image analysis programs to analyze the heterogeneity of MMP activity in a given cell population, and how that might change with different microenvironmental conditions or drug treatment.

In addition to matrix degradation, the Leight lab also studies the organization of ECM fibers in the tumor microenvironment. The ECM becomes organized and aligned during tumor progression and provides highways for invading tumor cells, yet the underlying mechanisms remain unclear. Leveraging the strength of OSU’s Comprehensive Cancer Center, we have led a collaborative effort to establish the role of the tumor suppressor phosphatase and tensin homolog (PTEN) in matrix alignment in a murine model and in breast cancer patients.

2022

26. Jones CE, Sharick JT, Sizemore ST, Cukierman E, Strohecker AM, Leight JL. A miniaturized screening platform to identify novel regulators of extracellular matrix alignment. Cancer Research Communications. Nov 2022. (Link)

25. Sharick JT, Atieh AJ, Gooch KJ, Leight JL. Click chemistry functionalization of self-assembling peptide hydrogels. Journal of Biomedical Materials Research Part A, Oct 10, 2022. (Link)

24. Nairon KG, DePalma TJ, Zent JM, Leight JL, Skardal A. Tumor cell-conditioned media drives collagen remodeling via fibroblast and pericyte activation in an in vitro premetastatic niche model. iScience 25 (7), 104645, 2022. (Link)

2021

23. Drain AP, Zahir N, Northey JJ, Zhang H, Huang P, Maller O, Lakins JN, Yu X, Leight JL, Alston-Mills BP, Hwang ES, Chen Y, Park CC, Weaver VM. Matrix compliance permits NF-kB activation to drive therapy resistance in breast cancer. J of Experimental Medicine, May 3, 2021. (Link)

22. Jones CE, Sharick JT, Colbert SE, Shukla VC, Zent JM, Ostrowski MC, Ghadiali SN, Sizemore ST, Leight JL. Pten regulates collagen fibrillogenesis by fibroblasts through SPARC. PLoS One, Feb 3; 16(2), 2021. (Link)

2020

21. Wormsbaecher C, Hindman AR, Avendano A, Cortes-Medina M, Jones CE, Bushman A, Onua L, Kovalchin CE, Murphy AR, Helber HL, Shapiro A, Voytovitch K, Kuang X, Aguilar-Valenzuela R, Leight JL, Song JW, Burd CJ. In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness. Breast Cancer Research, 2020. (Link)

2019

20. Casadei L, Calore F, Braggio DA, Zewdu A, Deshmukh AA, Fadda P, Lopez G, Wabitsch M, Song C, Leight JL, Grignol VP, Lev D, Croce CM, Pollock RE. MDM2 Derived from Dedifferentiated Liposarcoma Extracellular Vesicles Induces MMP2 Production from Preadipocytes. Cancer Research, 2019. (Link)

19. Campbell WA 4th, Deshmukh AA, Blum S, Todd L, Mendonca N, Weist JL, Zent J, Hoang TV, Blackshaw S, Leight JL, Fischer AJ. Matrix-metalloproteinase expression and gelatinase activity in the avian retina and their influence on Müller glia proliferation. Experimental Neurology, Jun 25; 320:112984, 2019. (Pubmed)

18. Fakhouri AS, Weist JL, Tomusko AR, Leight JL. High Throughput 3D Hydrogel Cell Encapsulation Assay for Measuring Matrix Metalloproteinase Activity. ASSAY and Drug Development Technologies, Apr 17(3): 100-115, 2019. (Link)

17. Fakhouri AS, Leight JL. Measuring Global Cellular Matrix Metalloproteinase and Metabolic Activity in 3D Hydrogels. Journal of Visualized Experiments, e59123, doi:10.3791/59123, 2019. (Link)

16. Jones CE, Hammer AM, Cho Y, Sizemore GM, Cukierman E, Yee LD, Ghadiali SN, Ostrowski MC, Leight JL. Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland. Neoplasia. Jan 21(1): 132–145, 2019. (Link)

2018

15. Deshmukh AA, Weist JL, Leight JL. Detection of Protease Activity by Fluorescent Peptide Zymography. Journal of Visualized Experiments, e58938, doi:10.3791/58938, 2018. (Link)

14. Deshmukh AA, Weist JL, Leight JL. Detection of proteolytic activity by covalent tethering of fluorogenic substrates in zymogram gels. Biotechniques. 64(5):203-210, 2018. (Link)

13. Barnhouse VR*, Weist JL*, Shukla VC, Ghadiali SN, Kniss DA, Leight JL. Myoferlin Regulates Epithelial Cancer Cell Plasticity and Migration through Autocrine TGF-β1 Signaling. Oncotarget. 9 (27):19209–19222, 2018. (Link)

12. Shin DS, Tokuda EY, Leight JL, Miksch CE, Brown TE, Anseth KS. Synthesis of microgel sensors for spatial and temporal monitoring of protease activity. ACS Biomaterials Science and Engineering. 4(2):378-387, 2018. (Pubmed)

11. Shukla V, Barnhouse V, Ackerman WE, Summerfield TL, Powell HM, Leight JL, Kniss DA, Ghadiali SN. Cellular Mechanics of Primary Human Cervical Fibroblasts: Influence of Progesterone and a Pro-Inflammatory Cytokine. Annals of Biomedical Engineering. Jan;46(1):197-207, 2018. (Pubmed)

2017

10. Leight JL*, Drain AP*, Weaver VW. Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response. Annu Rev Cancer Biol.1:313-334, 2017.

2015

9. Leight JL*, Tokuda EY*, Jones CE, Lin AJ, Anseth KS. Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition. Proc Natl Acad Sci U S A. 112(17):5366-71, 2015. (Pubmed)

8. Sridhar BV, Brock JL, Silver JS, Leight JL, Randolph MA, Anseth KS. Development of a Cellularly Degradable PEG Hydrogel to Promote Articular Cartilage Extracellular Matrix Deposition. Adv Healthc Mater. 4(5):702-13, 2015. (Pubmed)

2014

7. Tokuda EY, Leight JL, and Anseth KS. Modulation of matrix elasticity with PEG hydrogels to study melanoma drug responsiveness. Biomaterials. 35(14):4310-8, 2014. (Pubmed)

2013

6. Leight JL, Alge DA, Maier AJ, and Anseth KS. Direct measurement of matrix metalloproteinase activity in 3D cellular microenvironments using a fluorogenic peptide substrate. Biomaterials. 34(30):7344-52, 2013. (Pubmed)

2012

5. Leight JL*, Liu WL*, Chaturvedi RR, Chen S, Yang MT, Raghavan S, and Chen CS. Manipulation of 3D cluster size and geometry by release from 2D micropatterns. Cellular and Molecular Bioengineering. 5(3):299-306, 2012. (Pubmed)

4. Leight JL, Wozniak MA, Chen S, Lynch ML, and Chen CS. Matrix rigidity regulates a switch between TGF-β1-induced apoptosis and epithelial-mesenchymal transition.Molecular Biology of the Cell. 23(5):781-91, 2012. (Pubmed) Highlighted by Faculty of 1000, March 2012

2009

3. Gehler S, Baldassarre M, Lad Y, Leight JL, Wozniak MA, Riching KM, Eliceiri KW, Weaver VM, Calderwood DA, and Keely PJ. Filamin A-{beta}1 Integrin Complex Tunes Epithelial Cell Response to Matrix Tension. Molecular Biology of the Cell. 20(14): p3224-3238, 2009. (Pubmed)

2007

2. Johnson KR, Leight JL, and Weaver VM. Demystifying the Effects of a Three-Dimensional Microenvironment in Tissue Morphogenesis. Methods in Cell Biology. 83: p539-575, 2007. (Pubmed)

1. Janmey PA, McCormick ME, Rammensee S, Leight JL, Georges PC, and Mackintosh FC. Negative normal stress in semiflexible biopolymer gels. Nature Materials. 6(1):p48-51, 2007. (Pubmed)

Bold highlights Leight lab members

*both authors contributed equally to this work

Citations

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