Our lab utilizes mouse models to understand the causes and conditions that facilitate cancer initiation and progression arising from adult stem cells of the skin. Adult stem cells replenish and repair mammalian tissue throughout life and are often the founding cells of cancer. Our goal is to determine the necessitating steps that lead to the formation of a skin tumor and identify means through which we can interrupt this process to prevent cancer. Additionally, we are also interested finding points of potential targeted intervention on established tumors through both pharmacological and genetic methods. We also employ genetic techniques to fluorescently label and trace cells from the cancer cell of origin to the final transformed tumor cell. This method allows us to isolate and profile cells through numerous stages of tumorigenic transformation, in order to determine the molecular changes that occur throughout this process.
Our previous work identified hair follicle stem cells as particularly susceptible to tumorigenic transformation. In the context of Ras/p53 mediated skin cancer formation, hair follicle stem cells can act as cancer cells of origin, whereas their descendant progeny, the transit amplifying cell population, is completely resistant to transformation. Moreover, we determined that during the resting phase of hair follicle, stem cell quiescence can act as a natural block to tumor initiation. This process of tumor suppression via stem cell quiescence may apply to other organ systems, and in cases where stem cells cycle very rarely, this could account for cancer emergence in later stages of life.
By studying both tumor initiation and tumor progression in a number of different skin cancer models in vivo, we hope to identify methods to inhibit tumor initiation and progression.
White AC and Lowry WE. “Refining the role for adult stem cells as cancer cells of origin.” Trends in Cell Biology. 2015 Jan;25(1):11-20. Epub 2014 Sep 18.
White AC, Khuu JK, Dang CY, Hu J, Tran KV, Liu A, Gomez S, Zhang Z, Yi R, Scumpia P, Grigorian M, Lowry WE. “Stem cell quiescence acts a tumor suppressor mechanism in squamous tumors.” Nature Cell Biology. 2014 Jan;16(1):99-107. Epub 2013 Dec 15.
White AC and Lowry WE. “Exploiting the origins of Ras mediated squamous cell carcinoma to develop novel therapeutic interventions.” Small Gtpases. 2011 Nov 1;2(6):318-321.
White AC, Tran KV, Khuu JK, Dang CY, Cui Y, Binder S, Lowry WE. “Defining the origins of Ras/p53 mediated squamous cell carcinoma.” PNAS (Peer Reviewed, Direct Submission). 2011 May 3;108(18):7425-30. Epub 2011 Apr 18.
Lee R, Chang SY, Trinh H, Tu Y, White AC, Davies BS, Bergo MO, Fong LG, Lowry WE, Young SG. “Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes.” Human Molecular Genetics. 2010 Apr 15;19(8):1603-17. Epub 2010 Jan 27.
Yin Y, White AC, Huh SH, Hilton MJ, Kanazawa H, Long F, Ornitz DM. “An FGF-WNT gene regulatory network controls lung mesenchyme development.” Developmental Biology. 2008 Jul 15;319(2):426-36.
White AC, Lavine KJ, Ornitz DM. “FGF9 and SHH regulate mesenchymal VegfA expression and development of the pulmonary capillary network.” Development. 2007 Oct;134(20):3743-3752. Epub 2007 Sep 19.
White AC, Xu J, Yin Y, Smith CS, Schmid G, Ornitz DM. “FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains.” Development. 2006 Apr;133(8):1507-1517. Epub 2006 Mar 15.
Lavine KJ, White AC, Park C, Smith CS, Choi K, Long F, Hui CC, Ornitz DM. “Fibroblast growth factor signals regulate a wave of hedgehog activation that is essential for coronary vascular development.” Genes and Development. 2006 Jun 15;20(12):1651-66.
Zhang, X, Stappenbeck TS, White AC, Lavine KJ, Gordon JI, and Ornitz DM. “Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development.” Development. 2006 Jan;133(1):173-180. Epub 2005 Nov 24.
Lavine KJ, Yu K, White AC, Zhang X, Smith C, Partanen J, Ornitz DM. “Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo.” Developmental Cell. 2005 Jan;8(1):85-95.
Zhao S, Hung FC, Colvin JS, White A, Dai W, Lovicu FJ, Ornitz DM, Overbeek PA. “Patterning the optic neuroepithelium by FGF signaling and Ras activation.” Development. 2001 Dec;128(24):5051-60.
Colvin JS, White AC, Pratt SJ, Ornitz DM. “Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme.” Development. 2001 Jun;128(11):2095-106.