The lactate-NAD axis activate cancer associated fibroblasts by downregulating p62 [OLA ATAC-seq]

Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulate p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impaired poly(ADP-Ribose)-polymerase 1 (PARP1) activity. PARP1 inhibition blocked the poly(ADP-ribosyl)ation of the AP1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ rendered CAFs less active. PARP inhibitors, such as Olaparib, mimicked lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies utilizing Olaparib would benefit from strategies aimed at inhibiting CAF activity. ATACseq samples from WPMY-1 cells treated or not with olaparib for 4 days