Iannis (Ioannis) Aifantis, Salvador Aznar-Benitah, Eduard Batlle, Cédric Blanpain (organisateur), John E. Dick (organisateur), Peter Dirks, Michaela Frye, Elaine Fuchs, Richard Gilbertson, Margaret A. (Peggy) Goodell, Carla Kim, Barbara Marte (Senior editor, Nature, Londres), Emmanuelle Passegué, Karl Lenhard Rudolph, Frederic (Fred) de Sauvage, Andreas Trumpp, Doug Winton, Jing Yang
by Cedric Blanpain and John E. Dick
10 – 15 September, 2018
The symposium entitled “Stem Cells and Cancer” organized by Cédric Blanpain and John Dick was held at Les Treilles from September 10 to 15, 2018. The meeting aimed to discuss the advances that have taken place in the field of stem cells and their relationship with cancer initiation, tumor growth, metastatic spread, and response to anti-cancer treatments. The role of stem cells in aging, tissue repair and inflammation, and the high plasticity of stem cells during regeneration were also discussed. Many therapeutic perspectives of these research topics have been presented. The meeting brought together some of the most prestigious scientific figures in the field, including Elaine Fuchs, Salvador Aznar Benitah, Michaela Frye, Doug Winton, Carla Kim, KL Rudolph, Jing Yang, Cedric Blanpain, Peter Dirks, Eduard Batlle, Richard Gilbertson, Fred de Sauvage, Emmanuelle Passegué, Margaret A. Goodell, Iannis Aifantis, John E. Dick, and Andreas Trumpp. The scientific discussions were productive and lively with an excellent atmosphere. In conclusion, the Treilles meeting “stem cells and cancer” was a great success.
Keywords: stem cells, development, homeostasis, regeneration, cancer, diseases
Talks: titles & summaries
Iannis (Ioannis) Aifantis (New York University School of Medicine, USA) – Cell intrinsic and extrinsic regulation of leukemia initiation and progression
Salvador Aznar-Benitah (IRB Barcelona, Spain) – Adult stem cells in homeostasis, ageing and cancer: interplay between time, diet, and epigenetics
Eduard Batlle (IRB Barcelona, Spain) – Stems cells and tumor microenvironment in colorectal cancer
Cédric Blanpain, organisateur (IRIBHM / ULB, Brussels, Belgium) – Cancer Cell of origin and Tumor heterogeneity
John E. Dick, organisateur (Princess Margaret Cancer Centre, University Health Network, Toronto, Canada) – Stem Cells play a role in leukaemia from the beginning to the end
Peter Dirks (The Hospital for Sick Children, University of Toronto, Canada) – Mapping functional and molecular properties of brain tumour stem cells
Michaela Frye (University of Cambridge, UK) – The regulatory potential of RNA modifications in stem cells
Elaine Fuchs (The Rockefeller University, New York, USA) – Environmental impacts on skin stem cells
Richard Gilbertson (CRUK, Cambridge Institute, UK) – Mapping cancer origins – a route to prevention
Margaret (Peggy) Goodell (Baylor College of Medicine, Houston, USA) – Stem Cell Competition in Hematopoiesis
Carla Kim (Children’s Hospital Boston, USA) – Regulation of progenitor cells in the adult lung and in lung cancer
Emmanuelle Passegué (Columbia Stem Cell Initiative, Columbia University, New York, USA) – Hematopoietic stem cells in stress, disease and aging
Karl Lenhard Rudolph (Leibniz Institute on Aging – Fritz Lipmann Institute, Jean, Germany) – Epigenetic stress responses in stem cell aging
Frederic (Fred) de Sauvage (Genentech, San Francisco, USA) – Plasticity of cancer stem cells
Andreas Trumpp (HI-STEM gGMBH, German Cancer Research Center (DKFZ)) – Metabolism and Therapy Resistance
Doug Winton (CRUK, Cambridge Institute, UK) – Impact of Stem cell organisation on somatic mutational burden in intestine
Jing Yang (University of California San Diego, USA) – Epithelial-Mesenchymal Plasticity in Carcinoma Metastasis
Elaine Fuchs (Rockefeller University) summarized her lab’s research in which they identified the skin stem cells and their niches, and demonstrated that their interactions with their niches dictate both the molecular properties of each stem cell and its role in tissue regeneration. She showed that the critical genes controlling stem cells and lineage progression are rooted in chromatin dynamics and that stem cells retain epigenetic memory of inflammation that persists over an extended time period, and allows skin stem cells to respond more rapidly upon the next damage.
Salvador Aznar Benitah (IRB Barcelona) presented evidence that the function of stem cells is under a circadian control. This mechanism prolongs stem cell fitness. They have shown that perturbations in this clock mechanism occur during physiological aging, and result in a significant loss of stem cell function and that loss of cell identity is a hallmark of dermal aging, whereby dermal fibroblasts present adipogenic differentiation that severely impair their function.
Michaela Frye (University of Cambridge) discussed the importance of RNA modifications in the regulation of gene expression and the modulation of cell fate decisions. Some modifications in transfer RNAs are deposited in response to external cues and adapt global protein synthesis and gene-specific translational accordingly, thereby facilitating development. Aberrant deposition of these modifications can lead to human disease, including cancer.
Doug Winton (University of Cambridge) presented how the plasticity of intestinal secretory progenitors allows them to act as self-renewing stem cells, in particular during regenerative settings. He then described how somatic mutations allow to visualising clones in human colonic epithelium and discuss how high mutant allele frequencies can be achieved by biased behaviours that may contribute to cancer development.
Carla Kim (Harvard University) discussed how lung organoid culture allowed to uncover molecular mechanisms by which adult lung progenitor cells can be directed to differentiate by their surrounding microenvironment and to model lung diseases and lung cancer. She discussed her data showing that the histone methyltransferase G9a is a suppressor of lung tumor-propagating cells and cancer progression.
KL Rudolph (Fritz Lipmann Institute) talked about his new concept that the epigenome integrates responses to aging-associated, cell intrinsic changes (such as accumulation of molecular damages) as well as to aging-associated, cell extrinsic changes (such as increases in inflammatory signal in aging). Epigenetic alteration in stem cells in turn limit stem cell function in tissue maintenance and select for clonal dominance of altered stem cells. These altered stem cell clones will further aggravate defects in tissue maintenance during aging.
Jing Yang (UCSD) discussed the importance of epithelial-mesenchymal transition (EMT) in carcinoma metastasis. She presented evidence that reversible activation of EMT could promote breast tumor metastasis. Then she discussed how EMT could be regulated by both extracellular matrix cues and epithelial polarity.
Cédric Blanpain (Brussels University) showed how the chromatin and transcriptional landscape of the cancer cell at the origin of cancers influence tumor heterogeneity and EMT. He then presented evidence that EMT occurs through distinct cell transitional states that present different functions and are located in different niches are and regulated by distinct transcription factors. He finally shows how genetic mutations can stabilize the EMT states associated with metastasis.
Peter Dirks (University of Toronto) presented work in mouse and human models of brain cancer that support that quiescent brain tumour stem cells drive tumor growth in childhood and adult brain tumours. Brain tumour stem cells have a limited number of chromatin states that cross cut genetic diversity, suggesting that the abnormal brain tumour genome converges on a more limited number of programs that are essential for the tumorigenic state.
Eduard Batlle (IRB Barcelona) discussed how stromal cells help disseminated colorectal tumor cells to evade the attack of the immune system and the design of new therapeutic strategies based on targeting the tumor microenvironment such as TGFBR1 inhibitors combined with check-point blockade that promotes the eradication of metastasis.
Richard Gilbertson (University of Cambridge) demonstrated that different childhood brain tumours arise from specific progenitor cells in the developing nervous system, enabling brain tumours to be classified and treated with much greater precision. By extending this work to whole organism studies, he demonstrated that a combination of stem cell mutagenesis and organ damage determines cancer risk across different tissues.
Fred de Sauvage (Genentech) showed that despite the efficacy of Hedgehog Inhibitors in the treatment of Basal Cell Carcinoma (BCC), residual disease persists in some patients and may contribute to relapse when treatment is discontinued. Profiling experiments of residual tumor cells revealed that residual BCCs required Wnt pathway activation. Accordingly, co-treatment of BCC with vismodegib and a Wnt inhibitor further reduced the residual tumor burden achieving eradication of most tumors.
Emmanuelle Passegué (Columbia University) described how aberrant activation of hematopoietic stem cell (HSC) differentiation pathways in leukemia-initiating stem cells (LSC) contribute to disease development. In particular, she described how decreased Notch and increased Wnt activities synergize together to force leukemic SC to overproduce a population of myeloid-biased multipotent progenitors, which in turn drive malignant myeloid burden, and how normalization of these deregulated signalling activity could limit leukemia progression.
Margaret A. Goodell (Baylor College of Medicine) explored the concept of clonal hematopoiesis, discussing the broader findings in the field and provoking the group to think about different strategies through which a clone may prevail during cell competition. She then described the strategy through which HSCs with DNMT3A mutations prevail, through an advantage of self-renewal. Finally, she described the strategy that HSCs with mutations in PPM1D attain clonal dominance, through resistance to apoptosis in the context of a chemotherapeutic insult.
Iannis Aifantis (NY University) identified the transcriptional landscape of the bone marrow vascular, perivascular, and osteoblast niche populations at single cell resolution in both homeostasis and stress. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress, and illustrate the utility of single cell transcriptomic data in mechanically evaluating the regulation of hematopoiesis by discrete niche populations.
John E. Dick (University of Toronto) showed that pre-existing LSC survive therapy and cause relapse after therapy. The existence of clonally expanded pre-leukemic hematopoietic stem cells in the diagnosis blood sample of many leukemic samples predicted that it should be possible to identify individuals who are at risk for progressing to acute myeloid leukemia (AML) long before disease develops. They found a signature able to predict with high accuracy individuals who progress to AML, almost 10 years prior to AML development, offering the potential for future prevention trials.
Andreas Trumpp (DFKZ) presented the mechanisms regulating the resistance of pancreatic cancer to chemotherapy. The resistance is caused by up-regulation of CYP3A5 pathway activity, which metabolizes and inactivates these drugs intracellularly. Inhibition or CYP3A5 sensitizes cancer cells to chemotherapy. Two different CYP3A5 inhibitors have been identified and clinical trial testing these inhibitors have been initiated in pancreatic cancer patients.