The Hedgehog (Hh) pathway is critical for stem cell maintenance, embryonic patterning and growth in both invertebrates and vertebrates. Its deregulation is a characteristic trait of a number of cancers.
The transcriptional response to Hh signaling is mediated by zinc-finger transcription factors of the GLI family. GLI2 is thought to be the primary mediator of Hh signaling, and to regulate multiple cellular functions, such as cell cycle progression and apoptosis. GLI1, a Hedgehog pathway target, is often expressed at high levels in various cancers and represents a basis for therapeutic targeting of the Hedgehog pathway. The latter approach has only shown efficacy in tumors with activating mutations of the pathway.
Our work from the past few years demonstrates that GLI2 is a direct transcriptional target of TGF-β, driving loss of E-cadherin expression and increased tumor cell invasiveness and metastatic potential (Figure 1). We also demonstrated the importance of autocrine TGF-β signaling in melanoma invasion and metastasis, together with the demonstration of the effectiveness of specific therapeutic targeting of this pathway in pre-clinical therapeutic approaches against melanoma. Our work strongly suggests that TGF-b is capable of inducing a Hedgehog-like response in the absence of Hedgehog ligands, which could explain the failure of targeting the Hedgehog pathway in tumors expressing high levels of TGF-b.
The Team focuses on the elucidation of the complexity of signaling crosstalks that drive tumor progression, with a specific emphasis on TGF-b. A key interest resides in understanding how GLI2, a key mediator of Hedgehog signaling, contributes to the pro-metastatic effects of TGF-b in various tumor types, independent from Hedgehog signaling. Another major area of research consists in deciphering the intricate relationships between cell density-driven Hippo pathway activation and cellular responses to TGF-b as it relates to the control of YAP/TAZ-associated transcription in the context of epithelial-to-mesenchymal transition, and the acquisition of an invasive phenotype by tumor cells.