Tumor-associated Astrocytic YAP Signaling Prevents the Progression of Glioblastoma in Mice through Upregulating DHRS3 Signaling
Tumor-associated astrocytes (TAAs) are tightly involved in glioblastoma multiforme (GBM) progression, yet the molecular underpinnings governing TAAs-GBM crosstalk remain poorly defined. Here, we found that Yes-associated protein (YAP), a core effector of the Hippo pathway, was upregulated and functionally activated in TAAs of GBM patients and GBM model mice. YAP knockout in TAAs (YAPGFAP-CKO) accelerated GBM malignant progression and reduced the median survival of GBM-bearing mice, concomitant with increased recruitment of astrocytes and alternatively activated tumor-associated macrophages (TAMs) infiltration at the tumor margin. In in vitro assays, tumor-astrocyte-conditioned medium (T-ACM) from YAP-/- astrocytes promoted GBM cell proliferation and migration, whereas T-ACM from YAP-activated astrocytes exerted anti-tumorigenic effects. Mechanistically, we found that short-chain dehydrogenase/reductase 3 (DHRS3), a negative regulator of retinoic acid (RA) biosynthesis, was significantly downregulated in the TAAs of YAPGFAP-CKO GBM-bearing mice, accompanied with the upregulation of RA-inducible genes including retinoic acid receptors (RARs) in both TAAs and the surrounding tumor cells, suggesting that loss of astrocytic YAP in TAAs might potentially promote the metabolism of RA by downregulating DHRS3 to facilitate the progression of GBM through RAR signaling. Besides, pan RAR inverse agonist BMS493 indeed significantly impeded the pro-tumorigenic effect in GBM induced by YAP-/- T-ACM, whereas RAR agonist could enhance the growth of GBM notably. Finally, activation of astrocytic YAP-DHRS3 signaling potently inhibited GBM progression in vivo.