Signaling Mechanisms Controlling Bony Invasion and Bone Destruction in Oral Squamous Cell Carcinoma

Abstract

Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC commonly invades into the lymph nodes and mandible, which correlate with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly, cause large amounts of bone destruction and require extensive surgeries. Unfortunately, the molecular mechanisms of OSCC invasion into the mandible are not well understood and survival rates have not significantly improved for over 30 years. In a syngeneic model of murine OSCC, Parathyroid Hormone-related Protein (PTHrP), has been shown to be required for OSCC invasion into the mandible. Existing studies have identified the Hedgehog (Hh) transcription factor, Gli2 as the regulator of PTHrP and our previous work in breast cancer metastasis to bone suggest that TGFB may regulate Gli2 transcription. Here we demonstrate that Hh and TGFB signaling concomitantly regulate Gli2 and subsequently PTHrP in OSCC. Additionally, we have elucidated a mechanical signaling mechanism that controls Gli2 activation levels, where extra-cellular matrix rigidities similar to bone, but not basement membrane, causes an increase in ciliogenesis. We also demonstrate the feasibility of targeting Gli2 in vivo using GANT58 loaded microspheres to prevent bone destruction.