Karimnia et al. demonstratedthat photodestruction of stromal fibroblasts in a 3D coculture withPDAC cell lines enhanced tumor response to PDT. Additionally, under hypoxic conditions, typical of dense3D matrices as demonstrated herein, hypoxia-inducible factors (HIF-1αand HIF-2α) in cancer cells orchestrate broad genetic programsthat reprogram stromal cells via the expression of TGF-β, IL-1,PDGF, and bFGF, promoting the differentiation of normal fibroblastsinto CAFs. The gene discussed is EPAS1; the disease is cancer.