The Role of ACKR3 in Breast, Lung, and Brain Cancer

Neves, Maria G. P. M. S.; Fumagalli, Armando; Bor, Jelle van den; Marin, Philippe; Smit, Martine J.; Mayor, Federico

doi:10.1124/mol.118.115279

Cited by 32 publications

(43 citation statements)

References 61 publications

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“…These roles include a variety of developmental functions, homeostasis of the immune system by controlling the homing of hematopoietic stem cells, and regulation of the activation, differentiation, migration, and survival of leukocytes (Scholten et al, 2012;Koenen et al, 2019). Chemokine receptors are therefore key in inflammatory processes and are also involved in a number of immune and autoimmune diseases, including psoriasis, atherosclerosis, and allergies, among others (Murdoch and Finn, 2000); they are also considered to be important in cancer (Neves et al, 2019). Some chemokine receptors are also used by the human immunodeficiency virus (HIV) to enter into target cells (Scarlatti et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

et al. 2019

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Chemokine receptors belong to the class A of G protein-coupled receptors (GPCRs) and are implicated in a wide variety of physiologic functions, mostly related to the homeostasis of the immune system. Chemokine receptors are also involved in multiple pathologic processes, including immune and autoimmune diseases, as well as cancer. Hence, several members of this GPCR subfamily are considered to be very relevant therapeutic targets. Since drug discovery efforts can be significantly reinforced by the availability of crystal structures, substantial efforts in the area of chemokine receptor structural biology could dramatically increase the outcome of drug discovery campaigns. This short review summarizes the available data on chemokine receptor crystal structures, discusses the numerous applications from chemokine receptor structures that can enhance the daily work of molecular pharmacologists, and describes the challenges and pitfalls to consider when relying on crystal structures for further research applications. SIGNIFICANCE STATEMENT This short review summarizes the available data on chemokine receptor crystal structures, discusses the numerous applications from chemokine receptor structures that can enhance the daily work of molecular pharmacologists, and describes the challenges and pitfalls to consider when relying on crystal structures for further research applications.

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Section: Introductionmentioning

confidence: 99%

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

et al. 2019

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“…In the last, ACKR3 is found in neurons, astrocytes, and vascular cells 3 and plays a pivotal role in interneuron migration 4,5 and leukocyte entry into the brain parenchyma 6 . ACKR3 is over-expressed in numerous cancer types 7 , including glioma, where both its expression and activation have been positively correlated with increased proliferative state and invasiveness 8 .…”

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confidence: 99%

The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

et al. 2020

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The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in tumors promotes cell proliferation and invasiveness. The intracellular signaling pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by identifying the interactome of ACKR3. Here, we report that recombinant ACKR3 expressed in HEK293T cells recruits the gap junction protein Connexin 43 (Cx43). Cx43 and ACKR3 are co-expressed in mouse brain astrocytes and human glioblastoma cells and form a complex in embryonic mouse brain. Functional in vitro studies show enhanced ACKR3 interaction with Cx43 upon ACKR3 agonist stimulation. Furthermore, ACKR3 activation promotes β-arrestin2- and dynamin-dependent Cx43 internalization to inhibit gap junctional intercellular communication in primary astrocytes. These results demonstrate a functional link between ACKR3 and gap junctions that might be of pathophysiological relevance.

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“…Indeed, ACKR3 can inhibit tumor growth and progression by acting on chemokine bioavailability, or it can promote tumorigenesis by regulating the CXCR4 signaling [ 48 ]. Its role in glioma is now emerging [ 49 ]. ACKR3 expression is increased in GBM, especially in tumor cells and vessels, and correlate with a bad prognosis.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

Manini

Caponnetto

Dalla

et al. 2020

Cancers

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The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.

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The Role of ACKR3 in Breast, Lung, and Brain Cancer

Cited by 32 publications

References 61 publications

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

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