The combination of Wnt and TGF-beta pathway activation is sometimes but not always required to fully activate this ECM program in Ewing sarcoma cells, again pointing to the critical contribution of spatially and temporally dynamic tumor:TME crosstalk in regulating EWS::FLI1-dependent transcriptional states, tumor cell heterogeneity, and phenotypic plasticity (124). The gene discussed is FLI1; the disease is neoplasm.