Transcriptional control mechanisms that underlie normal development of epidermis, hair follicles, mammary glands, and epithelial carcinogenesis.
Cell fate in skin stem cells and basal cell carcinoma.
Cellular and molecular origins of melanoma initiation, clonal progression, and metastasis.
Transcriptional and chromatin control of epithelial stem cell self-renewal, differentiation, and skin and breast cancer.
Systems level approaches to uncover pathways that regulate melanin production in human skin and chemoresistance in melanoma tumors.
Redox regulation in melanocytes, melanoma, malignant pathogenesis, and drug resistance. Melanoma chemoprevention (national effort).
Regeneration of complex tissues and organs under normal conditions and in response to injury or disease.
The high rate of metastasis and recurrence among melanoma patients indicates the existence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. Here, we identify CD47 as
a regulator of melanoma tumor metastasis and immune evasion. Protein and gene expression analysis of clinical melanoma samples reveals that CD47, an anti-phagocytic signal, correlates with melanoma metastasis. Antibody-mediated blockade
of CD47 coupled with targeting of CD271+ melanoma cells strongly inhibits tumor metastasis in patient-derived xenografts. This therapeutic effect is mediated by drastic changes in the tumor and metastatic site immune microenvironments,
both of whichwhich exhibit greatly increased density of differentiated macrophages and significantly fewer inflammatory monocytes, pro-metastatic macrophages (CCR2+/VEGFR1+), and neutrophils, all of which are associated with disease
progression. Thus, antibody therapy that activates the innate immune response in combination with selective targeting of CD271+ melanoma cells represents a powerful therapeutic approach against metastatic melanoma.
Michael Ngo, Arum Han, Anita Lakatos, Debashis Sahoo, Stephanie Hachey, Kipp Weiskopf, Andrew Beck, Irving Weissman, Alexander Boiko
Cell Reports. 16(6):1701-16.
Reversible epithelial-to-mesenchymal transition (EMT) is central to tissue development, epithelial stemness, and cancer metastasis. While many regulatory
elements have been identified to induce EMT, the complex process underlying such cellular plasticity remains poorly understood. Utilizing a systems biology approach integrating modeling and experiments, we found multiple
intermediate states contributing to EMT and that the robustness of the transitions is modulated by transcriptional factor Ovol2. In particular, we obtained evidence for a mutual inhibition relationship between Ovol2 and
EMT inducer Zeb1, and observed that adding this regulation generates a novel four-state system consisting of two distinct intermediate phenotypes that differ in differentiation propensities and are favored in different
environmental conditions. We identified epithelial cells that naturally exist in an intermediate state with bidirectional differentiation potential, and found the balance between EMT-promoting and -inhibiting factors to
be critical in achieving and selecting between intermediate states. Our analysis suggests a new design principle in controlling cellular plasticity through multiple intermediate cell fates and underscores the critical
involvement of Ovol2 and its associated molecular regulations.
Tian Hong**, Kazuhide Watanabe**, Catherine Ha Ta, Alvaro Villarreal-Ponce, Qing Nie, Xing Dai
PLoS Comput Biol. 11(11):e1004569.
Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In this study, we identify a subset of human melanomas that
have loss-of-function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the
altered expression of inflammatory genes, resulting in decreased T cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a mechanism by which melanoma
cells modulate the immune microenvironment to promote continued growth.
Chi-Fen Chen, Rolando Ruiz-Vega, Priya Vasudeva, Francisco Espitia, Tatiana B. Krasieva, Sebastien de Feraudy, Bruce J. Tromberg, Sharon Huang, Chad P. Garner, Jie Wu, Dave S. Hoon, Anand K. Ganesan
Cell Reports. 18(10):2331-42.
Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from
myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte
transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid
fibroblasts either when treated with BMP or when placed with human hair follicles in vitro. Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans.
Maksim V. Plikus*, Christian F. Guerrero-Juarez, Mayumi Ito, Yun Rose Li, Priya H. Dedhia, Ying Zheng, Mengle Shao, Denise L. Gay, Raul Ramos, Tsai-Ching Hsi, Ji Won Oh, Xiaojie Wang, Amanda Ramirez, Sara E. Konopelski, Arijh Elzein, Anne Wang, Rarinthip June Supapannachart, Hye-Lim Lee, Chae Ho Lim, Arben Nace, Amy Guo, Elsa Treffeisen, Thomas Andl, Ricardo N. Ramirez, Rabi Murad, Stefan Offermanns, Daniel Metzger, Pierre Chambon, Alan D. Widgerow, Tai-Lan Tuan, Ali Mortazavi, Rana K. Gupta, Bruce A. Hamilton, Sarah E. Millar, Patrick Seale, Warren S. Pear, Mitchell A. Lazar, George Cotsarelis*
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