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Abstract :
[en] Chemokines are a superfamily of chemo-attractant cytokines playing critical roles in many pathophysiological
processes including cancer. The biological effects of chemokines are mediated through seven transmembrane
receptors coupled to G proteins (GPCR). Chemokine receptors are usually coupled to Gi but may also trigger
further signaling through β-arrestins. Tumor and stromal cells express diverse patterns of chemokines and
chemokine receptors. For instance, multiple evidences have linked the CXCR4-CXCL12 axis to initiation and
progression of various types of cancer, including gliobastomas. This aggressive malignant brain tumor derived
from glial cells is currently incurable, thus requiring innovative treatments.
Recently, CXCR7 has been identified as another high-affinity receptor for CXCL12 but also CXCL11, a
chemokine initially reported to bind exclusively to CXCR3. Interestingly, CXCR7 displays a propensity to form
homo- and hetero-dimers with CXCR4. CXCR3 binds CXCL11, CXCL10 and CXCL9 inducing or inhibiting
cell migration and proliferation or death depending on the cell type. These opposite behaviors were proposed to
be a consequence of the existence of three splice variants, CXCR3-A, CXCR3-B and CXCR3-alt. Some studies
put forward the possibility that CXCR3-A and CXCR3-B may be coupled to different G protein subtypes,
triggering distinct signaling pathways. Nevertheless, no direct evidences of such differential coupling have been
reported. Similarly to CXCR7, CXCR3-A was recently shown to heterodimerize with CXCR4. Several
important questions regarding CXCR3 biology remain elusive. For instance, the precise signaling pathways of
the different CXCR3 splicing isoforms, their ligand selectivity as well as the impact of receptor homo- and
hetero-dimerization on ligand binding and signaling properties require deep investigation. The aim of this project
is to decipher these molecular mechanisms in the context of glioblastoma pathophysiology.
