Microphysiological system modeling pericyte-induced temozolomide resistance in glioblastoma

Abstract Glioblastoma (GBM) is a malignancy with poor survival and high rates of chemoresistance. Temozolomide (TMZ), the standard-of-care chemotherapy for GBM patients, but GBM cells can be resistant to TMZ, resulting in limited clinical efficacy. Elucidating the complex mechanisms of TMZ chemoresistance in GBM requires novel in vitro models replicating the complex tumor microenvironment (TME). We present an multicellular 3D GBM model recapitulating the biomechanical characteristics of brain tissues and pericyte-mediated TMZ resistance. The composite hydrogel used to encapsulate GBM spheroids (U87, LN229, and PDM140), pericytes, or GBM spheroids with pericytes, mimics the rheological properties of brain tissues (G’∼800Pa and G”∼100Pa). When untreated, the GBM models remain viable and proliferative for 14 days. PDM140 spheroids were most sensitive to TMZ (IC 50 =73μM), followed by LN229 (IC 50 =278μM) and U87 (IC 50 =446μM). With pericytes, the viability of TMZ-treated GBM spheroids significantly increases by 22.7% for PDM140, 32.5% for LN229, and 22.1% for U87, confirming pericyte-induced GBM chemoresistance responses. The upregulation (380-fold) of C-C motif chemokine ligand 5 (CCL5) in pericytes upon TMZ treatment could explain the chemoresistance responses. This innovative brain-mimicking 3D GBM model represents a novel in vitro platform for testing the efficacy of TMZ and novel drugs targeting CCL5-mediated chemoresistance pathways in GBM.