Stem Cell Lineage Infidelity Drives Wound Repair and Cancer

Abstract

Summary Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement - granting privileges associated with both fates - is not only hallmark, but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Probing mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.

Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

“…Genetic alterations that mobilize SCs more rapidly are often associated not only with accelerated wound repair, but also increased cancer susceptibility 30 . Indeed, individuals with gain-of-function mutations in inflammasome components can show increased risk of epidermal cancers 31, 32 .…”

Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

“…In this view, the versatility of a stem cell in a wound response may then simply be a reflection of changes in this environment. When stem cells are removed from their native context, either in a wound response or in culture, they then must adjust their chromatin dynamics and change their program of gene expression in order to survive in their new environment (Adam et al, 2015; Ge et al, 2017). Given that not all epigenetic adjustments are rapid, this could account for why aging keratinocytes in vitro are initially readily distinguishable from their younger counterparts, but with time and passage in culture, these differences wane (Keyes et al, 2013).…”

“…Integrins α5β1 cluster at the leading edge of the keratinocyte, where they participate in polarizing cell shape and cytoskeletal movements needed for effective epithelial migration and fibronectin assembly (Aragona et al, 2017; Coles et al, 2006; Heller et al, 2014; Qiao et al, 2014). Finally, RNA-seq analyses of microdissected tissue in the migrating zone suggests that a number of metalloproteinases are expressed, where they likely function in the ECM remodeling that takes place in the wound repair process (Aragona et al, 2017; Ge et al, 2017; Hattori et al, 2009; Okada et al, 1997; Stevens and Page-McCaw, 2012). …”

“…However, following injury, when the systemic and local environments change dramatically, these stem cell populations display remarkable plasticity (Adam et al, 2015; Ge et al, 2017). Indeed, even if their own niche is not perturbed, nearby stem cells respond to wound-induced stimuli by exiting their niche and participating in re-epithelializing damaged tissue (Horsley et al, 2006; Ito et al, 2005; Jensen et al, 2009; Levy et al, 2005; Lu et al, 2012; Nowak et al, 2008; Page et al, 2013).…”

FOXN1 Transcription Factor in Epithelial Growth and Wound Healing

“…Besides that, injured and cancer tissues have similar gene signatures. It was recently shown that SC lineages acquire plasticity that enables their activation, which is facilitated by SOX9 and KLF5 transcription factors in both phenomena: wound healing and tumorigenesis (58).…”