Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

Abstract

Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.

Large-scale pan-cancer analysis reveals broad prognostic association between TGF-β ligands, not Hedgehog, and GLI1/2 expression in tumors

“…We established a role for both TGF-β signaling and GLI2 in driving melanoma invasion and metastasis, that could be targeted with TGF-β receptor inhibitors or by knocking down GLI2 expression [14][15][16]. Similar observations have since been reported for other tumor types, including ovarian and oral squamous cell carcinomas, that link GLI2 and TGF-β expression to tumor aggressiveness [17][18][19].…”

Hallmarks of Bone Metastasis

“…It is worth noting that the issue of bioavailability in the bone is more likely to be the limiting factor in targeting Wnt and Hedgehog signaling, since these pathways are physiologically switched off post-development and are frequently activated in tumor cells [87]. Advances in the field of nanoparticles hold promise for this avenue since several groups have identified effective inhibitors to the TGFβ [83, 88] and Hedgehog signaling pathways [89] that with nanoparticle encapsulation enable tumors to selectively uptake these inhibitors and prevent bone destruction.…”

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

“…Hedgehog (Hh) signaling is silenced in many adult tissues; however, during tumorigenesis, it is often reactivated (14). Canonical Hh signaling is induced by sonic, indian, or desert Hh ligands and functions via glioma-associated oncogene family zinc finger (GLI) proteins, the major transcriptional effectors of Hh signaling (14). GLI proteins contain activation (GLI1, GLI2, and GLI3) and repression domains (GLI2 and GLI3) (15), thus differentially affecting their downstream target genes.…”

“…GLI proteins contain activation (GLI1, GLI2, and GLI3) and repression domains (GLI2 and GLI3) (15), thus differentially affecting their downstream target genes. Hh signaling can also be induced by non-canonical pathways including transforming growth factor (TGF)β-induced signaling (14,16,17). Non-canonical Hh signaling by TGFβ (and Wnt) was shown to induce GLI2 expression and activation (14).…”