Hedgehog and Gli signaling in stem cells and cancer

Participants :

Cedric Blanpain, Paola Bovolenta, Frederic Charron, Joanna Fombonne, Isabel Guerrero, Alberto Gulino, Christopher Heeschen, Mien-Chie Hung, Anna Marie Kenney, Thomas (Tom) Kornberg, William (Bill) Matsui, Patrick Mehlen (organizer), Muriel Perron, Elissaveta Petrova, David Robbins, Ariel Ruiz I Altaba (organizer), Julien Sage, Frédéric (Fred) de Sauvage, Barbara Stecca, Alex Swarbrick, Pascal Théron, Rune Toftgard, Brandon Wainwright

Julien Sage Frederic Charron Alberto Gulino Isabel Guerrero Pascal THérond Rune Toftgard Paola Bovolenta Alex Swarbrick David Robbins Anna Marie Kenney Brandon Wainwright Cédric Blanpain Muriel Perron Ariel Ruiz i Altaba Christopher Heeschen William (Bill) Matsui Patrick Mehlen Elissaveta Petrova Frederic de Sauvage Barbara Stecca Mien-Chie Hung Joanna Fombonne Thomas (Tom) Kornberg Hedgehog and Gli signaling in stem cells and cancer

Review

Summary:  The meeting at Les Treilles on Hedgehog & Gli signaling in stem cells and cancer focused on recent advances in the understanding of signaling by Hedgehog morphogens in development and cancer. Novel results and extensive discussions focused on modes of signaling, pathway interactions, integration of signaling inputs, target regulation, small molecule modulators and clinical experience.

Key words:  Hedgehog, Gli, cancer, development, cell-cell communication, signaling, tumor, stem cells.

 

The Meeting in Les Treilles focused on Hedgehog signaling in development, stem cells and cancer. 22 scientists from Europe, America and Asia came together for one week to discuss recent findings in various fields, ranging from morphogen function and developmental fate decisions to anti-cancer therapies and clinical results.

Several exciting themes were developed in detail with vigorous discussions and many ideas for future experiments.

How morphogens act was a hot topic. Hedgehog has been proposed to move from cell to cell via different mechanisms. Secretion into the cellular space in the context of vesicles, lipids and multimers has been argued for, as well as transcytosis. New ideas about the possible existence of Hh in exosomes or extracellular vesicles associated to membrane protrusions or not were discussed. It is worth emphasizing the exciting possibility that long filopodia or cytonemes are essential for signaling. Elegant work in flies points in this direction.

Hh-Gli acts to specific different cell fates. For example, in the vertebrate nervous system its morphogenetic role is well established, being required first for all ventral cell inductions in the neural tube. Work on the retina in different organisms was also discussed, pointing to exciting roles in spatial specification and organization of pattern.

Normal stem cells pools from different organs in multiple organisms appear to require Hh-Gli signaling for expansion and self-renewal.  Similarly, work was discussed that further points to a key role of Hh-Gli signaling in humans and mice in the control of cancer stem cells in multiple tumor types, ranging from brain and skin to lung and colon.  The kinds of genes regulated by HH-GLI, as well as interactions with partners and parallel pathways, suggests a refined and intricate network that acts in a context-dependent fashion.

Indeed, one of the emerging exciting aspects of the meeting was the delicate and important interactions that this pathway has with other key signaling pathways known to regulate embryonic cell fate and cancer growth, such as WNT-TCF signaling.  Work was presented that provide different modalities for interactions, from mutual requirement to temporal switches, all being critical for cancer but at different stages and times.

As HH-GLI was discussed to be a driver of metastases, at least in colon cancer, the question of how metastases are controlled was a central focus of the meeting, ranging from presentations on endogenous metastases suppressors to the elaboration of the idea that a number of morphogen receptors are death-dependent receptors. This exciting idea was explored focusing on Hh signaling and different possible receptor combinations.

On the therapeutic front, several investigators presented exciting data on regulators of HH-GLI signaling, such as SUFUH and microRNAs, but also on novel small molecule regulators of different component so fhte HH-GLI pathway. These included small molecules that target SMOH, and extensive discussion focused on recent data on Basal Cell Carcinomas and other cancer types, including lung, breast, colon and brain tumors as well as leukemias.  Interestingly, other small molecules identified in screens target more downstream targets, raising the possibility that these could harbor additional specificity or bypass resistance to SMOH inhibitors.

Overall, this was an exceedingly exciting meeting, with great unpublished data presented that generates very positive interactions and great expectations in the field.  All the participants were enthusiastic about the format, content and organization and many inquired about the possibility to repeat the meeting in Les Treilles in 2-3 years time.

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