Abstract SY39-01: Stem cells in squamous cell carcinomas: Their biology, heterogeneity, and resistance to therapy

Abstract

Abstract Tissue stem cells self-renew long term and differentiate into one or more tissues. Many 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 govern tissue growth is of fundamental importance to our understanding of normal tissue maintenance and wound repair. Increasing evidence suggests that the regulatory circuitry governing the balancing act between quiescence and proliferation is often at the root of cancers. The hair follicle is an ideal model for dissecting how stem cells remain quiescent during times of minimal wear and tear, how these cells become mobilized during the cyclical bouts of hair growth and wound repair, and how the normal process of stem cell activation goes awry in cancer. We have identified and characterized at a molecular level an important stem cell niche within the hair follicle. We have mapped the chromatin landscape of these stem cells while they reside quiescently in this niche, and elucidated how this changes when the stem cells become activated to proliferate and progress along their lineage to generate short-lived progeny. We have also shown that when these stem cells exit their niche during wound repair, they undergo marked chromatin remodeling, a change functionally required to enable stem cells to survive in a stressful tissue environment. We have begun to uncover the underlying mechanisms by which stem cells receive these external signals from the wound microenvironment and transmit them to the nucleus to elicit chromatin remodeling. Intriguingly in cancer, the initial steps of wound repair are recapitulated, but the off signals that prompt stem cells to return to quiescence following repair are no longer operative. Our in vivo chromatin analyses have yielded important insights into the underlying mechanisms. These epithelial stem cells are known to be a source of squamous cell carcinomas (SCCs), which, as a class, are one of the most common and life-threatening cancers worldwide. Using mice as our model, we have applied our knowledge of normal skin stem cells to explore the tumor-initiating "stem cells" of SCCs. Remarkably, within the SSC, these tumor-initiating cells reside at the tumor-stroma interface, where they exist in two distinct states. The slower-cycling state occurs in stem cells close to the perivasculature, rich in TGF-β. These stem cells undergo SMAD2-signaling, express EMT markers, break down the basement membrane, and invade. They are also resistant to cisplatin chemotherapy. By contrast, the stem cells that do not receive the TGFβ signal proliferate faster but apoptose upon cisplatin treatment. Thus, within the developing SCC, heterogeneity due to an ever-changing tumor microenvironment elicits distinct behaviors in its stem cells, both of which contribute to tumor growth and malignancy. In the past year, we have continued to make inroads into understanding how tumor stem cells receive signals from their microenvironment that lead to changes in their behavior but also in their resistance to therapy. I will discuss our most recent discoveries, including transcriptional and translational remodeling in response to tumor stressful environments. Together, our multipronged approaches should be useful in our ever-growing endeavors to understand the underlying basis for squamous cell carcinomas, which are not only one of the most common but also one of the most life-threatening cancers worldwide. Citation Format: Elaine Fuchs. Stem cells in squamous cell carcinomas: Their biology, heterogeneity, and resistance to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY39-01.