Oncogenic signaling, DNA damage response and genetic instability
Genomic instability is a prominent source of genetic diversity within tumors, generating a diverse cell population that can be subject to selection in a given micro-environmental or therapeutic context. It can arise through various routes, leaving distinct genomic footprints and differentially affecting tumor evolution and patient outcome. One of the most important sources of genomic instability relies on the defective accuracy and transmission of genetic information to daughter cells when cells that are copying their DNA in preparation for division suffer from ‘replication stresses’ due to various external or endogenous impediments that slow or stall replication forks. This replication stress induces fork collapse, Double-Strand-Breaks (DSB) and chromosomal instability and is a major cause of pathologies including cancer, premature ageing and other disorders associated with genomic instability. It particularly affects genomic loci where progression of replication forks is intrinsically slow or problematic, such as chromosomal fragile sites, telomeres, and repetitive sequences.
While the emergence of variant cells, exacerbated by chromosomal instability, promotes tumor heterogeneity and drug resistance, extreme genetic instability appears deleterious for cell fitness and correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability.
CRCT researchers from the “Oncogenic Signaling, DNA Damage Response & Genetic Instability” research line are advancing this research line with originality since they are exploring the molecular changes in cells and tissues that cause replicative stress, limit excessive chromosomal instability and explain resistance to therapy in strong association with oncogenic signaling pathways, such RAS, RHOB, BRAF, PI3K, CHK1 and EGFR. They are also proposing molecular targets to design new strategies for cancer therapy, manipulating the DNA repair forces that limit excessive instability to fight cancer, and promoting the clinical application of they discoveries on these different fronts.
This research line is headed by Jean-Sébastien Hoffmann.
RNA and cancer
The control of gene expression is a biological process essential to all organisms. The genome of a cell contains all the information a cells needs to grow, divide and multiply. To access this information, the DNA has to be transcribed into RNA. RNAs can be divided into two classes:
- messenger RNAs (mRNAs), which are translated into proteins,
- and non-coding RNAs (ncRNAs), which are functional as RNA molecules rather than encoding proteins.
Gene expression in humans is complex and highly regulated. RNA molecules are known to regulate a variety of biological processes. Regulation of mRNAs is thereby achieved by different RNA-binding proteins (RBPs), non-coding RNAs, such as microRNAs (miRNAs) and long non coding RNA (lncRNAs) and epigenetic modifications.
CRCT researchers from the “RNA processing, epigenetics and gene expression “Axis 2 explore the dysregulation of these key players of the control of gene expression and their role in the alteration of the cellular landscape that can lead to cancer initiation, maintenance, progression, invasion and metastasis.
This research line is headed by Fabienne Meggetto.
Tumor microenvironment and metabolism
It is now well-admitted that tumors are heterogeneous in their composition, comprising in addition to cancer cells, stromal cells and extracellular matrices that can represent up to 90% of certain solid tumor mass. Yet, tumor microenvironment has started to be taken into account in the analysis of solid tumor biology and response to treatments for fifteen years only but nowadays represents a major field of research. The critical and still evolving role of the “niche” has been known for thirty years for hematopoietic stem cells, representing an invaluable source of knowledge. Concepts of “local” and “distant” niches whereby tumor cells set up juxtacrine and paracrine dialogs with stromal cells in the primary tumor, or endocrine signals with distant “pre-metastatic” sites, respectively, have emerged and greatly increased our understanding of the tumor biology at the scale of the whole organism.
CRCT comprises 11 projects aimed at understanding and tackling tumor resistance to treatments and metastasis with the goal to develop strategies that co-target tumor cells with their microenvironment. To do so, the biology of both tumor cells and stromal cells has to be studied in complex in vitro and in vivo models, whereby the direct and indirect interactions between the different cellular and acellular components truthfully mimic the human tumor biology. CRCT team Leader’s partnerships with IUCT clinical services are essential in the synergistic development of compulsory patient-derived models. With the nearby CREFRE animal facility, genetically-engineered models that develop spontaneous tumors also represent great pre-clinical tools for CRCT teams to test novel therapeutic drug combinations, before being translated to patients. Among others, models for myeloid acute and chronic leukemia, lymphoma, glioblastoma, breast, lung, melanoma, ovarian or pancreatic cancers are intensively developed by CRCT teams.
Specific focus and expertise concern the biology of mesenchymal stromal cells, cancer-associated fibroblasts, adipocytes or normal epithelial cells, exploring how they interact with tumor and other stromal cells, either directly or indirectly through extracellular matrices or vesicules and diffusible factors, to functionally impact on tumor cell aggressivity (reprogrammation & stemness, metastasis, resistance to treatments) or on immune cell function (recruitment, polarization and activation within the tumor). Understanding the biology of these dialogs, how they are generated within each cell partner (signaling, metabolism) and modulated by environment cues (oxygen and nutriment starvation) or by therapies targeting the tumor cells (targeted therapies or chemotherapies), is critical to design novel synergistic strategies aimed at therapeutic targeting both the tumor and stromal compartments.
This research line is headed by Corinne Bousquet.
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