Coupling Raman Spectroscopy and Acoustic Microscopy to Characterize Glioblastoma Resistance

Therapy resistance in glioblastoma is usually described in genetic or metabolic terms. Here we ask whether it also has a measurable biophysical form. Combining Raman spectroscopy with scanning acoustic microscopy on TRAIL-sensitive and TRAIL-resistant glioblastoma cells, we find that resistance carries both a biochemical and a mechanical signature: the resistant cells differ at protein, lipid and nucleic-acid bands, contain 4.1-fold more neutral lipid, and hold a high acoustic impedance that does not change when the drug is applied, while sensitive cells stiffen as they die. Because acoustic impedance is an absolute quantity and neither measurement requires a label, the approach offers a route to recognising resistant populations from their physical state alone.