Cytokine CCL2 secreted by cancer-associated fibroblasts augments temozolomide resistance in glioblastoma through ERK1/2 signaling.

The intricate tumor microenvironment largely influences chemoresistance in glioblastoma. Cancer-associated fibroblasts (CAFs) that modulate tumor progression have recently been identified as non-tumor stromal cells within the glioblastoma microenvironment. It remains unclear whether CAFs play a role in conferring chemoresistance to glioblastoma. The effects and mechanisms of CAFs on glioblastoma cells under temozolomide (TMZ) treatment are investigated by a series of patient-derived CAFs, orthotopic xenograft mouse models, and glioblastoma organoids (GBOs). Patient-derived cells have a transcriptomic and biomolecular profile of CAFs. CAFs promote temozolomide resistance in glioblastoma in vitro; these findings are consistent with results from intracranial tumor xenografts and GBO models. Mechanistically, CAFs express and secrete a significantly higher C-C motif chemokine ligand 2 (CCL2), which selectively enhances the activation of the ERK1/2 signaling in glioblastoma cells. Pharmacologically disrupting the CCL2-CCR2 axis or MEK1/2-ERK1/2 pathway effectively restores the therapeutic efficacy of temozolomide in glioblastoma cells and patient-derived GBOs. The decreased phosphor-ERK1/2 expression induced by trametinib treatment is also observed in glioblastoma cells following the CCL2-CCR2 axis inhibition. The present study suggests that targeting the CCL2/CCR2/ERK1/2 pathway may help overcome chemoresistance in glioblastomas caused by CAFs.