ACSN 2.0 Maps

Cell Cycle and DNA Repair Map UPDATED!

DNA repair mechanisms are highly affected and dysregulated in familial and sporadic cancers. In addition, coordination between DNA repair and cell cycle via checkpoints are often perturbed in cancers. An integrated DNA repair and cell cycle map is composed of interconnected modules representing cell cycle phases and checkpoint proteins, coordinating cell cycle and DNA repair activities. DNA repair machinery is presented by 10 pathways related to single strand and double strand DNA damage repair. The map consists of approximately 723 chemical species, 544 reactions and is based on 646 scientific papers.

Creators: Amélie Gelay and Laurence Calzone; Edited by: David Cohen, Nguyễn Hiển Anh, Inna Kuperstein
Contributors: François Radvanyi, Simon Saule, Janet Hall, Marie Ditreix, Marc-Henri Stern, ,Mounira Amor-Guéret, Wolf Heyer, J.P. de Villartay, Fillipo Roselli, Patricia Kannouche, Cyril Buhler, Amelie Croset, Maria Quanz, Murat Saparbaev

Cell Survival Map UPDATED!

Signalling pathways involved in cell survival are widely exploited by cancer, ensuring the viability of a cell in diverse conditions such as oxygen shortage. The cell survival map is composed of four major modules each divided into smaller functional sub-modules. The map depicts Growth factors signaling, PI3K/AKT/mTOR, MapK, Hedgehog (canonical and non-canonical) and Wnt (canonical and non-canonical) pathways and multiple crosstalks between them. The map consists 1967 chemical species and is based on 869 scientific references.

Creators: David Cohen. Module MAPK: Luca Grieco and Denis Thieffry
Contributors: Thierry Dubois, Gordon Tucker, Francisco Cruzalegui

Regulated Cell Death Map UPDATED!

The map represents mechanisms involved in all documented modes of regulated cell death (RCD). The map depicts biochemical triggers and upstream signalling as death receptors; mitochondria, glucose metabolism and DNA damage initiating different modes of programmed cell death. An addition layer of cell death signalling regulation by miRNAs is described on the map as well. The molecular mechanism executing each programmed cell death mode is represented in details. The map is composed of 26 functional modules. In total, the map contains 2657 species among them 1008 proteins, 260 genes, 93 miRNAs, 2020 reactions etc. and based on original information retrieved from 600 scientific papers.

Creators: Simon Fourquet; Edited by: Inna Kuperstein, Luca Grieco
Contributors: Boris Zhivotovski

Telomere Maintenance Map NEW!

Telomeres are protein-DNA complexes at the ends of linear chromosomes, essential for genome stability. They consist of a G-rich repeat that contains the TTAGGG sequence repeatedly. Telomeres have two main roles: to prevent chromosome to chromosome fusions as well as to protect the chromosomic ends from being detected as double strand breaks by the DNA repair machinery. Telomere maintenance, in terms of their length and DNA damage, constitutes two central points that allow cell proliferation. Cells that bypass this quality control become immortalized: either by activation of proliferation despite telomere shortening or damage, or by elongation of the telomere. Immortalization is a key step in tumorigenesis. Even if telomere elongation itself does not trigger growth deregulation, immortalization is a crucial point for cancer cells as a 90% of them expressed telomerase and the other 10% appear to replicate their telomeres through other means. Therefore, telomeres are involved in cancer but also in orphan diseases known as telomeropathies. 153 chemical species interconnected by 105 reactions describe in this map how telomeres are maintained.

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EMT and Senescence Map UPDATED!

Epithelial-to-Mesenchymal transition (EMT) is a normal process during embryonic development that can be involved during wound healing, fibrosis or cancer invasion. During EMT, tightly zipped and largely immobile epithelial cells transform into highly mobile mesenchymal cells. The process requires excessive cytoskeletal rearrangement, changing of cellular polarity from apical-basal into front-back to gain cell motility. Transforming cell detaches from neighboring cells by disrupting cell-cell adhesion. During cell migration, new adhesion points to the matrix outside are continuously established. EMT and cell motility map is a comprehensive map of molecular interactions taking place in the processes of EMT and cell migration. We depicted the pathways involved in oxidative stress, senescence and EMT and crosstalk between these processes. The map contains around 700 proteins, 1500 reactions, 11 functional modules and it is based on approximately 1400 scientific papers.

Creators: Nguyen Hien Anh
Contributors: Inna Kuperstein, Philippe Chavrier, Anne-Vincent Salomon

Invasion and Motility Map NEW!

Tumorigenesis is a gradual multistep process that enables cells to acquire new biological capacities that will allow tumor formation and dissemination for metastases formation. To invade distant organs, tumor cells have to acquire migration capacity, which is provided by the EMT associated with cytoskeleton reorganization and modification of cellular adherence. This map depicts signaling pathways by which a cancer cell can achieve the features that lead to metastasis. Also, the phenotypes that occur before metastasis are present, such as proliferation, apoptosis resistance, and cell survival among others. Due to the PRL-3 (or PTP4A3) phosphatase has been described to play key roles in this processes, we thoroughly depict this protein. This map consists of 117 proteins, 364 reactions and it is based on approximately 60 papers.

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Dendritic Cell Map NEW!

Dendritic cells (DC) are innate immune cells that can have both myeloid and lymphoid origin. The main marker for mature dendritic cells is CD83+. Immature dendritic cells express among others HLA-DR, CD80, CD86, CD1a, CD40, CD14, CD11c, CD209, ILT3. Similarly to macrophages, dendritic cells possess phagocytic abilities, and can produce inflammatory cytokines as IFNs, IL12, etc. The major role of dendritic cells in anti-tumor response is antigen presentation and T-cell activation. The map consists of approximately 491 chemical species, 346 reactions and is based on 333 scientific papers.

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Natural Killer Cell Map NEW!

Natural killers (NK) are big granular lymphocytes which can be cytotoxic for tumor cells. The markers of this cell type are specific NK-receptors as NKp30, NKp46, NKG2D, etc. The main role of NK cells in innate immunity is elimination of cells lacking MHC1 molecules that therefore cannot be recognized by T-cells. NK are stimulated by the target cells expressing NK receptors activating ligands such as MICA, MICB, etc. The activity of NK cells is modulated by inflammatory cytokines as IL15, IL12, produced by macrophages and dendritic cells. NK cells secrete granules contains lytic enzymes (granzymes, perforin, granulysin, etc) and express apoptosis inducers TRAIL and FASL. Presence of active NK cells in cancer is correlated with good prognosis. To escape NK control, tumor cells express immunosuppressive ligands as MIF, IL10, TGFB and downregulation of NK ligands expression that collectively inhibit cytotoxic activity of NK cells. Pro-tumor polarization of NK cells is not described in the literature, however suppressed NK cells are incapable to reject tumor cells and therefore indirectly promote cancer progression. The map consists of approximately 567 chemical species, 377 reactions and is based on 336 scientific papers.

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Macrophages are the major immune component of leucocyte infiltration in tumor. The main markers of macrophage are CD11b+, CD68+, LGALS+ and CD163. Anti-tumor polarization of macrophages is related to their ability to recognize and to reject tumor cells by phagocytosis, represent tumor antigens on the cell surface and induce T-cell response. Macrophages produce cytotoxic agents such as Reactive Oxygen Species and Nitrite Oxide, secrete chemokines as CXCL-8, CCL2, CCL3, etc and attract immune cells into the TME. It addition, they express inflammatory cytokines as TNF, IL12, IL1, etc. facilitating local immunity activation. Tumor associated macrophages (TAMs) can also act as pro-tumor agents, expressing tumor stimulating growth factors as PDGF, EGF, VEGF, FGF, producing immunosuppressive molecules as IL10 and TGFB, that induce angiogenesis and matrix remodelling in TME and consequently facilitate metastatic process.
Myeloid-derived suppressor cells (MDSC) represent heterogeneous population of myeloid cells. In general, the role of MDSC in TME is similar toTAMs. Their main markers are CD33+, CD15+ (granulocytic), CD14+ (monocytic), CD34+ and CD11b+. MDSC suppress T-cell response and Natural killers activity via TGFB signaling and arginine depletion from TME. In addition, MDSCs induce EMT and angiogenesis and participates in matrix remodelling via VEGF and MMPs secretion. MDSC mostly show a pro-tumor activity, therefore presence of this cell type in tumor is correlated with poor clinical prognosis. The map consists of approximately 588 chemical species, 457 reactions and is based on 214 scientific papers.

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