General Biology Seminar -- Kroc Lecture

Stem cells (stem cells) have the ability to self-renew long term and differentiate into one or more tissues. Typically, stem cells are used sparingly to replenish cells during normal homeostasis. However, even stem cells that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How stem cells balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. Increasing evidence suggests that the regulatory circuitry governing this balancing act is at the root of some types of tumors both in mice and in humans.

The skin is an excellent model system to understand how stem cells function in normal tissue generation and how this process goes awry in cancer. We've identified stem cell niches within the epidermis, hair follicle and sweat glands. We've learned that different niches become activated in response to different types of injury, and that during normal homeostasis, stem cell behavior is controlled not only through cues received from their microenvironment but also through signals emanating from their differentiating lineages. We've been dissecting how a series of extrinsic signals triggers a cascade of transcriptional changes that govern stem cell activation during tissue development, homeostasis and hair regeneration. Our findings provide new insights into our understanding of the process of stem cell activation, and in so doing have revealed mechanisms which are also deregulated in a variety of different human cancers. Our goal is to understand how stem cells start and stop making tissue, and how this changes in cancer and in drug resistance when cells acquire the ability to overcome the molecular brakes that operate in normal tissue stem cells. Our recent discoveries on this topic have led us to the realm of identifying and characterizing cancer stem cells (tumor-initiating cells) of squamous cell carcinomas (stem cells) of the skin.  We developed a novel method to rapidly knockdown genes specifically in skin and oral progenitors, enabling us to screen not only the differences between cancer and normal stem cells, but also the myriad of gene alterations surfacing from the Human Cancer Sequencing project on head and neck squamous cell carcinomas. Our screens have illuminated new oncogenes and tumor suppressors for stem cells, among the most prevalent and life-threating cancers world-wide that include cancers of lung, esophagus, breast, cervix, prostate, throat and oral tissues. Our findings are unearthing new targets for cancer therapeutics.