The present focus of the Skin Stem Cell/Epigenomics Laboratory of the BWH Program in Dermatopathology is identification of novel strategies to harness and control skin stem cells in the fight against cancer, defective wound healing, and severe forms of skin inflammation. We are leveraging past discoveries and current insights to this end, with particular attention to addressing the following critical questions in skin stem cell biology:
- How can skin cancer stem cells be identified and therapeutically eliminated?
- How can epidermal and dermal stem cells be stimulated to promote regenerative wound healing?
- How can skin stem cell targeting by immune pathways be thwarted to treat and prevent devastating forms of dermatitis such as psoriasis and graft-versus-host disease?
To this end, we have developed a strategic infrastructure that addresses all three issues in a synergistic, integrated, multidisciplinary and highly collaborative manner. For example, we and our collaborators have identified the first biomarker for for melanoma stem cells (Nature 2008), cancer-intrinsic expression of key immune checkpoints on melanoma stem cells (e.g. PD-1, see figure; Cell 2015), and epigenetic pathways involved in melanomagenesis (Cell 2012, NEJM 2016), all of which we are now exploring with the goal of developing smart combinatorial therapies that seek out and destroy the cells that matter in terms of driving melanoma virulence and recurrence. The same marker that identifies melanoma stem cells is also integral to physiologic skin cells critical to regenerative healing responses. Accordingly our current efforts also encompass strategies to enlist these stem cells in the reformation of damaged skin, an initiative in collaboration with the Harvard Stem Cell Institute that emphasizes understanding and therapeutic reversal of age-related skin stem cell and related repair deficiencies (also see https://hsci.harvard.edu/skin-program-1). Finally, we have found skin stem cells to be primary drivers of proliferative anomalies that underlie psoriasis and the cytotoxic injury that is the basis for cutaneous graft-versus-host disease, and these insights provide pathways for transformative therapeutic approaches for disease prevention. Harnessing the epigenome and deploying technological strategies that leverage highly multiplexed imaging, 3-D bioprinting, and gene sequencing further enhance these current research directions.