Ramiro Iglesias-Bartolome, Ph.D.
Our lab research focuses on elucidating the signaling mechanisms that control and drive tissue specific stem cell self-renewal and differentiation and their connections to tumor initiation and growth. In particular, our goal is to identify particular G-protein-coupled receptors (GPCRs) and their linked signaling partners that function as master regulators of epithelial stem cells during skin development, tissue homeostasis and malignant transformation.
1) epithelial stem cells, 2) signaling, 3) GPCRs, 4) mTOR, 5) squamous and basal cell
carcinoma, 6) skin
By using a combination of in vitro cell culture systems and animal models we are elucidating these signaling mechanisms that control and drive epithelial stem cell self-renewal and differentiation. Our focus at this moment is on G-protein-coupled receptors (GPCRs) and their signaling partners. GPCRs are the largest family of cell-surface molecules involved in signal transduction, playing central roles in numerous physiological processes and pathological conditions along with their associated G proteins. Since GPCRs are the direct or indirect target of more than 25% of therapeutic drugs on the market, they represent a unique potential target for the pharmacological intervention of stem cell activity.
Most GPCRs relay their signal by coupling to heterotrimeric Gα, β and subunits. Gα proteins are classified into four different families: Gαs, Gαi/o, Gαq/11 and Gα12/13. We have recently demonstrated that among Gα proteins, Gαs plays a central role in coordinating self-renewal and differentiation in epithelial stem cells. In mice, conditional epidermal deletion of the gene coding for the Gαs protein (Gnas) or inactivation of its signaling partner protein kinase A (PKA) are alone sufficient to cause an aberrant expansion of the stem cell compartment, resulting in the rapid formation of basal cell carcinoma (BCC). These findings reveal that Gαs-PKA function as part of a tumor-suppressive axis, limiting the proliferation of epithelial stem cells and maintaining hair follicle and skin homeostasis. Furthermore, they indicate that GPCRs may be involved in differentiation and tumorigenicity within the epidermal stem cell compartment.
Our major goal is to identify particular GPCRs and their linked signaling partners that function as master regulators of epithelial stem cells during skin development and tissue homeostasis, and their connection to malignant transformation and cancer. Our approaches include a variety of animal models and primary cell culture systems, synthetic biology methods, gene expression profiling by RNA sequencing, high-throughput screenings, microscopy and biochemical assays.
Selected Key Publications
YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity..Nature Communications. 11(1): 1472, 2020. [ Journal Article ]
Activation of G-Protein Coupled Receptor–Gαi Signaling Increases Keratinocyte Proliferation and Reduces Differentiation, Leading to Epidermal Hyperplasia.Journal of Investigative Dermatology. S0022-202X(19)33386-X: 2019. [ Journal Article ]
Inactivation of a Gα(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis..Nature Cell Biology. 17(6): 793-803, 2015. [ Journal Article ]
- Science Translational Medicine. Vol. 10, Issue 451,: 2018. [ Journal Article ]
mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis.Cell Stem Cell. 11(3): 401-414, 2012. [ Journal Article ]
|James Hoy Ph.D.||Postdoctoral Fellow (CRTA)|
|Katherine M. Lund B.S.||Postbaccalaureate Fellow|
|Maria Del Pilar Pedro Ph.D.||Postdoctoral Fellow (Visiting)|
|Yao Yuan B.S.||Special Volunteer (Graduate Student)|