The largest reservoirs of adult stem cells reside in skin. Throughout life, they renew the body’s protective barrier, regenerate hair in cyclical bouts and repair surface wounds. Fuchs studies where stem cells come from and how they make and repair tissues. She explores how stem cells communicate with immune, dermal, and other cells in their environment, and how communication malfunctions in aging and cancers, with an aim to advance therapeutics.
Fuchs’ lab couples in vitro studies with classical genetics, RNAi, and CRISPR-Cas technologies in mice to study the biology of skin stem cells. Her research employs high throughput genomics, single cell sequencing, live imaging, cell biology and functional approaches to unravel the pathways that balance stem cell maintenance and differentiation and to explore aberrant routes in aging and cancers. Her team investigates how stem cells establish unique chromatin landscapes and programs of gene expression, and how this shifts in response to changes in their local environment. They seek to discover the activating signals from neighboring cells that instruct skin stem cells when to make hair and when to repair epidermal injuries. Conversely, inhibitory cross talk tells the stem cells when to stop making tissue and rest. Their findings are accelerating the development of therapeutics to enhance wound repair.
After elucidating the positive and negative signaling pathways that need to be turned on and off at the right time and place for adult skin stem cells to become activated to regenerate tissue, Fuchs’ group focused on what happens when these signals are deregulated. They learned that cancer cells hijack the basic mechanisms that enable stem cells to replenish dying cells and to repair wounds.
A major focus of the lab is on squamous cell carcinomas, among the most common and life threatening of human cancers worldwide. The group first used high throughput genomics to delineate the features of so-called cancer stem cells. They then devised technology that permits high-throughput functional screens for oncogenes, tumor suppressors, and microRNAs in mice. By identifying mutations that selectively fuel cancer growth and showing that these alterations also occur in related human cancers, Fuchs hopes her research will lead to new therapeutics that target cancer stem cells without affecting tissue stem cells.
By studying early steps in malignancy, the group discovered that invading blood vessels and associated inflammatory cells transmit aberrant signals. Nearby tumor-initiating cells respond by reducing proliferation, invading stroma, and resisting chemotherapy. Further away, tumor stem cells grow faster but are more sensitive to drugs. This leads to differences in stem cell behavior within developing tumors that arises from heterogeneity in the microenvironment rather than from variations in genetic mutations.
How do these stromal aberrations affect the transcriptional, epigenetic, and translational programs of stem cells during tumor progression? How do these changes confer drug resistance, and how do they affect epithelial polarity, adhesion, and invasiveness within the tumor? Does the epigenetic and translational heterogeneity in tumor stem cells that arises from local variations in the stroma contribute to subsequent genetic heterogeneity within cancers? What is the importance of immune cell cross talk with stem cells in wound repair versus cancer? As the group answers these questions, they will continue to uncover new links to understanding the process of wound repair, as well as tumor progression and metastasis.