TGF-β and Oncogenesis

Mauviel

Alain Mauviel Team Leader Tel:

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.

Figure 1
Figure 1

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.

Key publications

Year of publication 2018

Saber Ben Mimoun, Alain Mauviel (2018 Mar 17)

Molecular mechanisms underlying TGF-ß/Hippo signaling crosstalks – Role of baso-apical epithelial cell polarity.

The international journal of biochemistry & cell biology : 75-81 : DOI : S1357-2725(18)30060-8

Year of publication 2015

Flore Nallet-Staub, Xueqian Yin, Cristèle Gilbert, Véronique Marsaud, Saber Ben Mimoun, Delphine Javelaud, Edward B Leof, Alain Mauviel (2015 Mar 9)

Cell density sensing alters TGF-β signaling in a cell-type-specific manner, independent from Hippo pathway activation.

Developmental cell : 640-51 : DOI : 10.1016/j.devcel.2015.01.011

Year of publication 2013

Carole Y Perrot, Delphine Javelaud, Alain Mauviel (2013 Feb 1)

Overlapping activities of TGF-β and Hedgehog signaling in cancer: therapeutic targets for cancer treatment.

Pharmacology & therapeutics : 183-99 : DOI : 10.1016/j.pharmthera.2012.10.002

Year of publication 2011

Delphine Javelaud, Vasileia I Alexaki, Sylviane Dennler, Khalid S Mohammad, Theresa A Guise, Alain Mauviel (2011 Aug 23)

TGF-β/SMAD/GLI2 signaling axis in cancer progression and metastasis.

Cancer research : 5606-10 : DOI : 10.1158/0008-5472.CAN-11-1194

Year of publication 2010

Vasileia-Ismini Alexaki, Delphine Javelaud, Leon C L Van Kempen, Khalid S Mohammad, Sylviane Dennler, Flavie Luciani, Keith S Hoek, Patricia Juàrez, James S Goydos, Pierrick J Fournier, Claire Sibon, Corine Bertolotto, Franck Verrecchia, Simon Saule, Veronique Delmas, Robert Ballotti, Lionel Larue, Philippe Saiag, Theresa A Guise, Alain Mauviel (2010 Jul 21)

GLI2-mediated melanoma invasion and metastasis.

Journal of the National Cancer Institute : 1148-59 : DOI : 10.1093/jnci/djq257
All publications