Prolonged Stem Cell Lineage Plasticity Underlies Cancer Progression

During wound repair, resident stem cells temporarily favor cell growth and proliferation over differentiation. Tumors exploit this normal process to maintain uncontrolled growth, but the mechanisms underlying the homeostatic shift of stem cells in both wound repair and tumorigenesis are unknown. Using mouse skin as a model, Ge and colleagues utilized the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) coupled with RNA and chromatin immunoprecipitation sequencing to compare in vivo chromatin states in homeostatic, wound-induced, and squamous cell carcinoma (SCC) stem cells. SCC stem cells had distinct accessibility profiles compared with those of homeostatic hair follicle and epidermal stem cells, and binding motifs for SOX9, normally expressed only in the hair follicle lineage, and KLF5, normally expressed in the epidermis stem cell lineage, were highly accessible in SCC stem cells. SCC stem cells coexpressed both SOX9 and KLF5, and CRISPR/Cas9-mediated deletion of Sox9 or Klf5 in SCC stem cells markedly impaired tumor growth in vivo and proliferation and invasion in vitro, confirming that lineage plasticity contributes to tumor maintenance. Of note, lineage plasticity marked by coexpression of SOX9 and KLF5 also occurred in wound-induced stem cells but was transient and reverted to homeostatic patterns as wounds healed. Accessible chromatin in both wound-induced and SCC stem cells contained unique enhancer elements and was enriched for binding motifs of stress-induced transcription factors such as ETS2, which is known to be required for SCC maintenance and phosphorylated by ERK1/2 during wounding. ETS2 was sufficient to induce lineage plasticity, and sustained ETS2 activity, which occurs in the setting of constitutive MAPK signaling caused by HRAS mutations in SCC, maintained lineage plasticity and commissioning of tumor-specific enhancers. In addition to providing insight into how tumor-associated stem cells lock in what is typically a transient wound-induced stem cell state in the skin, these findings suggest that drivers of sustained lineage plasticity represent potential therapeutic targets.

Ge Y, Gomez NC, Adam RC, Nikolova M, Yang H, Verma A, et al. Stem cell lineage infidelity drives wound repair and cancer. Cell 2017;169:636–50.e14.

• ©2017 American Association for Cancer Research.