Crosstalk between CXCR4/ACKR3 and EGFR signaling in breast cancer cells

A better understanding of the complex crosstalk among key receptors and signaling pathways involved in cancer progression is needed to improve current therapies. We have investigated in cell models representative of the major subtypes of breast cancer (BC) the interplay between the chemokine CXCL12/CXCR4/ACKR3 and EGF receptor (EGFR) family signaling cascades. These cell lines display a high heterogeneity in expression profiles of CXCR4/ACKR3 chemokine receptors, with a predominant intracellular localization and different proportions of cell surface CXCR4+, ACKR3+ or double-positive cell subpopulations, and display an overall modest activation of oncogenic pathways in response to exogenous CXCL12 alone. Interestingly, we find that in MDA-MB-361 (luminal B subtype, Her2-overexpressing), but not in MCF7 (luminal A) or MDA-MB-231 (triple negative) cells, CXCR4/ACKR3 and EGFR receptor families share signaling components and crosstalk mechanisms to concurrently promote ERK1/2 activation, with a key involvement of the G protein-coupled receptor kinase 2 (GRK2) signaling hub and the cytosolic tyrosine kinase Src. Our findings suggest that in certain BC subtypes, a relevant cooperation between CXCR4/ACKR3 and growth factor receptors takes place to integrate concurrent signals emanating from the tumor microenvironment and foster cancer progressio

The stress connection in cancer: the adrenergic fuelling of breast tumors

Cancer progression involves complex interactions between tumor cells and the surrounding microenvironment. Chronic psychosocial stress and sympathetic nervous system activation lead to abnormal catecholamine release, impacting tumor cells directly and indirectly and fuelling cancer-promoting effects. However, the same adrenergic Receptor (AR) that mediate these effects could also convey exercise-related beneficial changes. Epidemiological studies show conflicting associations between stress, AR inhibitors, and breast cancer (BC) metastatic progression. Adrenergic sympathetic stress triggers sustained inflammatory and hypoxic-related signaling pathways, alters function and distribution of immune cell populations, and remodels blood vessels, leading to immunosuppression and premetastatic site formation. Activated AR initiate feedback loops with tyrosine kinase receptors and chemokine receptors, affecting stem-related transcription factors, pro-inflammatory mediators, angiogenic factors, and energy metabolism regulators, promoting tumor growth and invasion. Understanding molecular mechanisms of agonistic and antagonistic AR ligands and crosstalk with other signaling pathways is crucial for developing effective therapies targeting adrenergic-driven BC progressionP2022/BMD-7209/INTEGRAMUNE-CM, SEV2016-064

Cell-Type Specific GRK2 Interactomes: Pathophysiological Implications

G protein-coupled receptor kinase 2 (GRK2) is emerging as a key hub in cell signaling cascades. In addition to modulating activated G protein-coupled receptors, GRK2 can phosphorylate and/or functionally interact with a complex network of cellular proteins in a cell-type and physiological context-dependent way. A combination of such canonical and noncanonical interactions underlies the participation of this kinase in the control of cell migration, proliferation or metabolism and in integrated processes at the tissue or whole organism levels, such as angiogenesis, cardiovascular function, or insulin resistance, among others. Its role as a signaling node and the fact that altered levels of GRK2 are detected in a variety of pathological conditions put forward this protein as a potentially relevant diagnostic and therapeutic targe