Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.

ABSTRACT: Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1⁺ cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys¹²³ (K123) enhances its recognition of cis-acting elements, increases chromatin binding,

SUBMITTER: Zhao D 

PROVIDER: S-EPMC12810638 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature