Développement, cancer et cellules souches
Colloque organisé par Martine Roussel (St Jude, Danny Thomas Research Center, Memphis) et Hans Clevers (Hubrecht Institute, Utrecht) du 23 au 28 août 2010
Yann Barrandon, Eduard Battle, Hans Clevers, Bruce A. Edgar, Riccardo Fodde, Harry Heimberg, Joerg Huelsken, Philippe Jay, Luis F. Parada, Martine Roussel, Owen Sansom, Charles J. Sheer, Rune Toftgard, Johan va Es, Maarten van Lohuizen, Fiona Watt
The theme of the meeting was inspired by the ever increasing role played by tumor suppressor pathways, such as those induced by Ink4a/Arf and p53, the Polycomb repressors of transcription, Bmi1 being one example, and developmental signaling pathways, including those activated by Sonic Hedgehog, Wnt and Notch in the regulation of cell fate and stem cell maintenance. It is by now increasingly apparent that deregulation of these pathways contributes to cancer.
The meeting co-organized by Drs. Hans Clevers and Martine F. Roussel assembled a number of internationally renowned scientists from Europe including Belgium (Harry Heimberg), England (Fiona Watt), France (Philippe Jay), Germany (Bruce Edgar), Scottland (Owen Sansom), Spain (Eduard Batlle), Sweden (Rune Toftgard), Switzerland (Joerg Huelsken and Yann Barandon) and The Netherlands, (Riccardo Fodde, Maarten Van Lohuizen, Johan Van Es and Hans Clevers), and from the USA, (Charles Sherr, Luis Parada and Martine Roussel). Using state of the art technologies in primary cell culture, novel in vitro and in vivo imaging tools and animal models that faithfully recapitulate the human disease, participants identified and characterized the function of, regulators of proliferation and tumor suppression, and specific protein markers of stem and progenitor cells during normal development in mammals and flies and in human cancers. Speakers discussed published and unpublished results from studies in different tissues, including brain, colon, intestine, liver, pancreas and skin.
Stem cells were one of the focuses of the meeting. Embryonic stem cells are defined as totipotent meaning that they are able to give rise to a complete organism. Embryonic stem cells exist only briefly in the early embryo, but can be expanded in cell culture. Adult stem cells are committed to a specific tissue but multipotent meaning that they can give rise to multiple cell types in a given tissue: for instance neuronal stem cells can give rise to astrocytes, glia and granule neurons but not blood cells or intestinal cells. Cancer stem cells resemble normal stem cells. They exist in tumors and are believed to be the driving force behind tumor growth, cancer relapse and metastasis.
Drs Maarten Van Lohuizen and Charles J. Sherr kicked of the meeting by introducing the role of general regulators of cell proliferation and differentiation in stem and progenitor cells and how their deregulation induces cancers. Bmi1, a global repressor of transcription or polycomb repressor was discussed by Dr Van Lohuizen in the context of development and cancers. Bmi1 that was discovered from a retroviral integration site is required to maintain cells in the stem-like state and to prevent stem cells from differentiating. As a result, Bmi1 is found overexpressed in many cancers in which stem cells fail to differentiate or progenitor cells re-acquired stem cell markers and self-renewal. Charles Sherr described the role of the Arf/p53 tumor suppressor pathway in the B cell lymphomas subtype, B-ALL. Although the Arf/p53 pathway is well recognized as a potent tumor suppressor pathway and is disrupted in all human cancers, its role during tissue homeostasis is less well defined. Sherr presented novel unpublished data for an unexpected critical role for Arf expression in normal spermatogenesis.
Several speakers addressed different aspects of colon and intestinal homeostatis and how disruption of the canonical Wnt , Notch or Ephrin pathway play roles in colorectal cancers. Several stem cells were identified in intestinal crypts that gave rise to all cell types of the intestine. Since his discovery of the bona-fide marker of intestinal stem cells, Lgr5, Hans Clevers and his team, including Johan Van Es, have developed sophisticated mouse models that make use of in vivo cell imaging to conclusively demonstrate that Lgr5 is the specific identifier of intestinal stem cells. Their laboratory and other speakers, including Owen Sansom, Philippe Jay, Juerg Huelsken, Riccardo Fodde and Harry Heimberg also demonstrated how aberrant activation of the Wnt pathway induces cancers of the digestive track, in particular colorectal cancers as well as cancers of the pancreas and the liver. Eduard Batlle evaluated the role of the Notch pathway and Eph B/Ephrin signaling in the intestine. Bruce Edgar identified stem cells in the Drosophila gut demonstrating that signaling pathways regulating gut homeostasis is well conserved during evolution.
In the skin, distinct stem cells are located in the inter-follicular epidermis, sebaceous gland and hair follicle. At steady state or during homeostasis, each pool of stem cell is restricted to their specific compartment. However, after stress or in response to injury, each different stem cell compartment identified by the markers Lgr5, CD34, Label retention, Lgr6, Blimp1 and lrig1/MTS24 can make all the cells of the hair follicle. Fiona Watt used chamber grafts to grow and reconstitute skin and use lineage tracing in wholemount epidermis to identify stem cells and their function in the epidermis. Yann Barrandon presented his experience and challenges in skin grafts in burned patients and how our understanding of skin biology may help in improving the outcome of transplants in skin. Rune Toftgard dissected the role of Hedgehog (Hh) signaling in the skin. He showed that Lgr5 positive cells respond to Shh that drives proliferation of secondary germ stem cells in the bulge. He also found that Hh signaling was important for wound healing: Lgr5+ stem cells labeled out of the bulge contributed to wound healing. Repopulation of the wound required Lgr5 positive stem cells and long term contribution occurs from Lgr5 and Lgr6 progenies. He showed that the wound environment induced a reprogramming of lgr5+ stem cells progeny enhancing the development of basal cell carcinomas.
Luis Parada identified neuronal stem cells in gliomas. By specifically targeting mutations found in human gliomas in mouse neuronal stem cells by sophisticated genetic tricks, mice rapidly developed aggressive gliomas. However, when mutations were targeted to the non-stem cell compartment, gliomas did not develop. These data clearly demonstrated that targeting neuronal stem cells was key to tumor development and that human gliomas must be induced by mutations in stem cells. In contrast to gliomas, medulloblastoma occur in progenitor cells that are committed to the granule neuron progenitor fate. Martine Roussel discussed her experience developing mouse models of medulloblastoma and the identification of the BMP pathway as a key regulator of progenitor and tumor cells differentiation and how this pathway can be used for differentiation therapy in brain cancers.
In summary, using different biological systems skin, colon, bone marrow, liver, pancreas or brain, participants to this meeting have made significant progress in the identification of stem cells and their niche, of cancer stem and tumor-propagating cells and the signaling pathways that control their maintenance, self-renewal and differentiation. Several speakers are using this novel information and new models of cancer to identify small compounds that target specific proteins with the goal of using them for targeted therapy in human cancers. This was truly a very stimulating and exciting meeting in a fabulous setting which from informal discussions with the participants has fostered collaborations and friendship among scientists that normally do not interact and participate in the same scientific meetings.