Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumours that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. Schematically, an intrinsic (driven by genetic events that cause neoplasia) and an extrinsic (driven by inflammatory conditions which predispose to cancer) pathway link inflammation and cancer. Smouldering inflammation in the tumour microenvironment contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, response to hormones and chemotherapeutic agents. As such, cancer-related inflammation (CRI) represents a target for innovative diagnostic and therapeutic strategies. We surmise that CRI represents the seventh hallmark of cancer. - 1. Mantovani A, Allavena P, Sica A, Balkwill F Cancer-Related Inflammation. Nature 454: 436-444, 2008. 2. Mantovani, A., Romero, P., Paluka, AK., Marincola, FM. Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771-783, 2008. 3. Biswas S.K. and Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as paradigm. Nat Immunol 2010: 11, 889-896. 4. Biswas S.K. and Mantovani A.Orchestration of metabolism by macrophages. Cell Metab. 2012: 15: 432-437. 5. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012, 122:787-95. Speaker affiliation: University of Milan - Istituto Clinico Humanitas, IT

Rap GTPases are Ras-family GTPases and play crucial roles in regulating cell adhesion/polarity and gene activation in a variety of cell contexts (Adv. Immunol. 2007). Rap signaling is essential for normal lymphohematopoiesis of all lineages, including myeloid, B- and T-lineage cells (Blood 2008a, 2009). Spa-1 (Sipa1) is a principal Rap-specific GTPase-activating protein (GAP) (JBC 1999, J. Biochemist. 2003), and deregulated Rap activation by Spa-1-defciency results in a spectrum of lymphohematopoietic malignancies due in part to enhanced c-Myc expression with increased genomic instability in hematopoietic progenitors (Cancer Cell 2003, Immunity 2006, Cancer Res. 2008, Cancer Sci. 2010). Recent analysis also reveals that excessive Rap signaling due to overexpression of Rap GTP/GDP exchange factor (C3G) in Spa-1-defciency causes aberrant homing of hematopoietic stem cells (HSCs) on BM transplantation. Raphigh HSCs preferentially home to thymus and spleen rather than BM unlike normal HSCs. Most notably, the Raphigh HSCs develop Notch-dependent T-cell acute lymphoblastic leukemia (T-ALL) with frequent Notch mutations, highly reminiscent of human T-ALL (Blood 2008b). The T-ALL genesis absolutely requires thymic microenvironment, in that Raphigh HSCs transplanted in athymic nude mice show extramedullary hematopoiesis in the spleen but never develop T-ALL. Rap signaling is crucial for the continuous Notch processing/activation and therefore maintenance of leukemic potential of T-ALL cells. In this presentation, I shall focus on the mechanisms of Notch activation by Rap signaling and provide a novel molecular target for controlling human T-ALL. Speaker affiliation: Kyoto University Graduate School of Medicine, JP

An orthologue of activation-induced cytidine deaminase (AID) was, evolutionarily, the first enzyme to generate acquired immune diversity by catalyzing gene conversion and probably somatic hypermutation (SHM). AID began to mediate class switch recombination (CSR) only after the evolution of frogs. Recent studies have revealed that the mechanisms for generating immune and genetic diversity share several critical features. Meiotic recombination, V(D)J recombination, CSR, and SHM all require H3K4 trimethyl histone modification to specify the target DNA. Genetic instability related to dinucleotide or triplet repeats depends on DNA cleavage by topoisomerase 1, which also initiates DNA cleavage in both SHM and CSR. These similarities suggest that AID hijacked the basic mechanism for genome instability when AID evolved in jawless fish. Thus, the risk of introducing genome instability into non-immunoglobulin loci is unavoidable but tolerable compared to the advantage conferred on the host of being protected against pathogens by the enormous immunoglobulin diversification. Speaker affiliation: Kyoto University Graduate School of Medicine, JP

Homologous recombination (HR) plays the essential role in repairing DNA damage that occur during DNA replication as well as in shuffling homologous chromosomes during meiosis. Efficient HR requires perhaps more than 100 proteins, as several novel HR factors have been yearly identified. We have defined the role of individual factors in HR by taking a reverse genetic approach using the chicken DT40 B cell line. This line has an extraordinary characteristic, as Jean-Marie Buerstedde as well as I found that chicken B cell lines including DT40 all displayed extremely efficient gene targeting. Our studies have uncovered the functions of the following HR factors: (1) Inactivation of RAD51 recombinase or the MRN/CtIP complex leads to numerous mitotic chromosomal breaks leading to cell death, indicating the essential role of these HR factors in genome maintenance. (2) Simultaneous disruption of multiple DNA polymerases such as PolH/PolN/PolQ and PolH/PolK/PolZ did not down-regulate gene targeting but often decreased the efficiency of HR-mediated immunoglobulin V gene diversification (Ig gene conversion), indicating that DNA-synthesis is not a rate-limiting step in HR-mediated gene targeting. (3) Ig gene conversion as well as nontemplated hypermutation is triggered by replication blockage at AID-induced abasic sites without accompanying by double-strand break formation. (4) Cells deficient in both MUS81 and XPF nucleases displayed severe genome instability due to defective completion of HR, indicating that recombination intermediates such as the Holliday junction may be frequently formed during mitotic HR. (5) We firstly revealed the critical role of ubiquitination in the initiation of HR by having analyzed the phenotype of cells deficient in UBC13. Speaker affiliation: Kyoto University Graduate School of Medicine, JP

Owing to early detection and intervention, most patients of early stage colon cancer are now cured completely. However, colon cancer is still lethal for many patients whose disease has progressed to the metastatic stage. Colon cancer progresses through a series of multi-step genetic/epigenetic changes.

We earlier constructed Apc716 knockout mice, a model for human FAP. Using the model, we found the polyp adenoma morphogenetic mechanisms, and demonstrated the role of COX-2 in adenoma expansion. Importantly, we found that COX-2 is expressed exclusively in the fibroblasts of tumor stroma rather than in the epithelial cells at this early stage.

To study the role of TGF-β signaling in colon cancer, we introduced a Smad4 knockout mutation into the Apc716 knockout mice, and found that their intestinal polyp adenomas become locally invasive adenocarcinomas. This was caused by recruitment of bone marrow-derived CCR1+ cells that produce MMP9. Furthermore, essentially the same mechanism appears to help disseminated colon cancer cells to colonize in the liver. Interestingly, treatment of the Apc/Smad4 mice with a CCR1 inhibitor suppressed the metastatic colonization of colon cancer cells in the liver. To investigate the mechanisms that stimulate metastasis by colon cancer epithelium, we have screened for and found a novel metastasis suppressor Aes that has turned out to be an endogenous inhibitor of Notch signaling. In colon cancer tissues, cancer cells express abundant Notch receptors whereas their ligands such as Jagged1 and Delta4 are expressed by the tumor stroma on vascular endothelial cells and smooth muscle layers. These results collectively indicate that from early stages of colon cancer progression, tumors expand, invade and metastasize through the interactions with their microenvironment in multiple modes. Speaker affiliation: Kyoto University Graduate School of Medicine, JP

Cutting-edge research is increasingly being performed globally. EMBO Global Activities increases awareness among scientists outside Europe about the excellent opportunities for doing research and collaborating with researchers in Europe. In the long term, EMBO envisions Europe as a prime destination for scientists throughout the world.

In the context of EMBO Global Activities, EMBO and EMBC engage in cooperation agreements with partner countries, which are based on mutual interest for stronger interactions and facilitating new opportunities for exchange. In this presentation, recent interactions with selected Asian countries will be highlighted. Speaker affiliation: EMBO

DNA alterations are usually associated with oncogenesis, yet controlled DNA instability is required for meiosis and a functional immune system. Base modifications of cytosine are an important aspect of chromatin biology, as they can directly regulate gene expression, while DNA repair ensures that those modifications retain genome integrity. The cytosine DNA deaminase AID causes targeted DNA demethylation when in combination with DNA repair competent extracts. Mechanistically this is achieved by inducing base alterations at or near the epigenetic mark, with the lesion being resolved either via single base substitution involving base excision repair (BER), or a more efficient processive polymerase dependent repair. This novel approach to DNA demethylation is supported by AID’s association with the clamp loader PCNA - a processivity factor, landing platform, and key regulator of DNA repair pathway choice. Because PCNA can be modulated by AID and thereby altering DNA repair pathway choice, the context of DNA damage - chromatin and protein complexes, may hold the key of how a lesion turns pathological. AID and APOBECs directly contribute to the mutation load of the cancer genome, which was identified from the footprint they leave in the DNA, and can be regulated by broad stimuli such as hormones. Because AID/APOBECs are needed for a healthy immune system, it places them the center of the balance between short term immune survival and long-term genetic pathologies. Speaker affiliation: IFOM

Progression of malignant tumors towards an aggressive phenotype is critically reliant upon tumor stroma reactivity. Among the most prominent cell type within the tumor stroma are cancer-associated fibroblasts (CAFs). The activity of CAFs have been found to play multifaceted roles in promoting cancer progression including the production of growth factors and chemokines and the remodeling of the extracellular matrix. A major unsolved question is the origins of these CAFs. We have developed a transgenic mouse model that mimics many of the cardinal features of a cutaneous tumor early in the metastatic cascade via the overexpression of the transcription factor Snail in epidermal keratinocytes of the skin. Snail is expressed in a wide variety of carcinomas and its embryological role in inducing an epithelial-mesenchymal transition (EMT) is often invoked as the mechanism by which it contributes to tumorigenesis. Recent work suggests that Snail has a major role in the generation and maintenance of cancer stem cell properties. We found that expression of Snail in epidermal keratinocytes can also affect the local microenvironment resulting in the activation of fibroblasts in the underlying dermal compartment of the skin that reproduces the hallmarks of CAFs. Surprisingly, these activated fibroblasts are not the result of a Snail induced EMT. Recapitulation of Snail-mediated fibroblast activation in vitro has led to the identification of a number of potential novel players leading to the formation of CAFs. Understanding the etiology of CAFs and their downstream effects has important implications for the development of anticancer therapies. Speaker affiliation: IFOM-inSTEM Joint Research Laboratory, National Centre for Biological Sciences, Bangalore, India

The Spindle Assembly Checkpoint is activated in the presence of up to one kinetochore unattached to the spindle microtubules. The checkpoint guarantees that sister chromatids are inherited evenly among daughter cells, and thus helps preventing the arising of aneuploidy. The observation that one single unattached kinetochore can completely arrest cell cycle progression lead to the hypothesis that some amplification mechanism might contribute together with the signal originated at the kinetochores to halting the cell cycle machinery. We have previously shown such a positive feedback loop in vitro, and we have then moved to confirm its presence in vivo. However, our results show that the positive feedback loop is silent in vivo. Instead, we observe that the same elements involved in the putative loop contribute to the stabilization of the checkpoint signal. Our results suggest that one single unattached kinetochore might be able to fully arrest cell cycle progression without the need of cytoplasmic amplification, but rather by creating a very stable end-product of the checkpoint. Speaker affiliation: IFOM

The idea to create IFOM has a long history that was conditioned by the creation of the institutions that allowed its financing and creation. And I must go all the way back to July 10, 1965 when I personally brought the articles of constitution to the notary Alessandro Guasti of the AIRC, Italian Association for Cancer Research. The association was immediately a great success and thanks to very low membership fees and a very strong message about the usefulness of research for cancer therapy, personified by Umberto Veronesi, it was possible to reach one million members across Italy in only a few years. From the start, the important issue was strict monitoring of the scientific aspect of the distribution of funds collected. This success made the organisation realise that it was possible and appropriate to create also a foundation, the FIRC, Italian Foundation for Cancer Research, with the aim of collecting more funds than was possible with normal membership dues. I must say that this too had a rapid success and, even back then, the idea emerged that perhaps the FIRC, together with AIRC, could have their own laboratories to manage directly. The foundation did not waste time and already in 1988 it had created an organising committee, coordinated by Professor Pier Paolo Di Fiore, for the creation of an institution that would gather the institutions in the Milan area that had the potential for studies and research in molecular oncology.

Presentation of the IFOM executive project occurred on June 8, 1999 in the Alessi room of Palazzo Marino with the presentation of the entire IFOM feasibility project by Professor Pier Paolo Di Fiore and Ing. Jacopo Vittorelli, president of the FIRC. While restructuring was ongoing, laboratory operations were initiated immediately using a floor of the building that was already manageable, even if not yet perfect and renovated. This was very useful for validating several instruments and research agendas and conducting a trial run of what was to come. In effect, we called this little operation “the little IFOM”. The other very important part was the inauguration of the complex which took place on April 9, 2003 with presentation not only of the executive program, but also of the scientific program of the IFOM itself.