scholarly journals Collective invasion induced by an autocrine purinergic loop through connexin-43 hemichannels

2020 ◽  
Vol 219 (10) ◽  
Author(s):  
Antoine A. Khalil ◽  
Olga Ilina ◽  
Angela Vasaturo ◽  
Jan-Hendrik Venhuizen ◽  
Manon Vullings ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Purinergic Signaling ◽  
Akt Signaling ◽  
Cell Junctions ◽  
Junction Protein ◽  
Collective Invasion ◽  
Leader Cell

Progression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell–cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells express the gap junction protein connexin-43 (Cx43), yet whether Cx43 regulates collective invasion remains unclear. We here show that Cx43 mediates gap-junctional coupling between collectively invading breast cancer cells and, via hemichannels, adenosine nucleotide/nucleoside release into the extracellular space. Using molecular interference and rescue strategies, we identify that Cx43 hemichannel function, but not intercellular communication, induces leader cell activity and collective migration through the engagement of the adenosine receptor 1 (ADORA1) and AKT signaling. Accordingly, pharmacological inhibition of ADORA1 or AKT signaling caused leader cell collapse and halted collective invasion. ADORA1 inhibition further reduced local invasion of orthotopic mammary tumors in vivo, and joint up-regulation of Cx43 and ADORA1 in breast cancer patients correlated with decreased relapse-free survival. This identifies autocrine purinergic signaling, through Cx43 hemichannels, as a critical pathway in leader cell function and collective invasion.

scholarly journals Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

2019 ◽  
Author(s):  
Antoine A. Khalil ◽  
Olga Ilina ◽  
Angela Vasaturo ◽  
Jan-Hendrik Venhuizen ◽  
Manon Vullings ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Cell Activity ◽  
Collective Invasion ◽  
Leader Cell ◽  
Adenosine Nucleotide

AbstractProgression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell-cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells co-express adherens junctions and connexin-43 (Cx43) gap junctions in vitro and in patient samples, yet whether gap junctions contribute to collective invasion remains unclear. We here show that Cx43 is required for chemical coupling between collectively invading breast cancer cells and, by its hemichannel function, adenosine nucleotide release into the extracellular space. Using molecular interference and rescue strategies in vitro and in orthotopic mammary tumors in vivo, Cx43-dependent adenosine nucleotide release was identified as essential mediator engaging the nucleoside receptor ADORA1, to induce leader cell activity and collective migration. In clinical samples joint-upregulation of Cx43 and ADORA1 predicts decreased relapse-free survival. This identifies autocrine nucleotide signaling, through a Cx43/ADORA1 axis, as critical pathway in leader cell function and collective cancer cell invasion.Graphical abstract

scholarly journals Energetic regulation of coordinated leader–follower dynamics during collective invasion of breast cancer cells

2019 ◽  
Vol 116 (16) ◽  
pp. 7867-7872 ◽  
Author(s):  
Jian Zhang ◽  
Kayla F. Goliwas ◽  
Wenjun Wang ◽  
Paul V. Taufalele ◽  
Francois Bordeleau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Energy Level ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Metabolic Regulation ◽  
Collective Behaviors ◽  
Cellular Energy ◽  
Collective Invasion ◽  
Leader Cell

The ability of primary tumor cells to invade into adjacent tissues, followed by the formation of local or distant metastasis, is a lethal hallmark of cancer. Recently, locomoting clusters of tumor cells have been identified in numerous cancers and associated with increased invasiveness and metastatic potential. However, how the collective behaviors of cancer cells are coordinated and their contribution to cancer invasion remain unclear. Here we show that collective invasion of breast cancer cells is regulated by the energetic statuses of leader and follower cells. Using a combination of in vitro spheroid and ex vivo organoid invasion models, we found that cancer cells dynamically rearrange leader and follower positions during collective invasion. Cancer cells invade cooperatively in denser collagen matrices by accelerating leader–follower switching thus decreasing leader cell lifetime. Leader cells exhibit higher glucose uptake than follower cells. Moreover, their energy levels, as revealed by the intracellular ATP/ADP ratio, must exceed a threshold to invade. Forward invasion of the leader cell gradually depletes its available energy, eventually leading to leader–follower transition. Our computational model based on intracellular energy homeostasis successfully recapitulated the dependence of leader cell lifetime on collagen density. Experiments further supported model predictions that decreasing the cellular energy level by glucose starvation decreases leader cell lifetime whereas increasing the cellular energy level by AMP-activated kinase (AMPK) activation does the opposite. These findings highlight coordinated invasion and its metabolic regulation as potential therapeutic targets of cancer.

scholarly journals Rb Suppresses Collective Invasion, Circulation and Metastasis of Breast Cancer Cells in CD44-Dependent Manner

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e80590 ◽  
Author(s):  
Kui-Jin Kim ◽  
Alzbeta Godarova ◽  
Kari Seedle ◽  
Min-Ho Kim ◽  
Tan A. Ince ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dependent Manner ◽  
Collective Invasion

SDF-1α regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3245-3252 ◽  
Author(s):  
Anabella L. Moharita ◽  
Marcelo Taborga ◽  
Kelly E. Corcoran ◽  
Margarette Bryan ◽  
Prem S. Patel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Connexin 43 ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Contact Inhibition ◽  
Enzyme Linked Immunosorbent Assay ◽  
Hematopoietic Regulation

Abstract Breast cancer cells (BCCs) show preference for the bone marrow (BM). An animal model showed 2 populations of BCCs in the BM with regard to their cycling states. An in vitro model of early BC entry into BM showed normal hematopoiesis. Here, we show a critical role for BCC-derived SDF-1α in hematopoietic regulation. The studies used a coculture of BM stroma and BCCs (cell lines and stage II BCCs). Northern blots and enzyme-linked immunosorbent assay (ELISA) showed gradual decreases in SDF-1α production in BCCs as they contact BM stroma, indicating partial microenvironmental effects caused by stroma on the BCCs. SDF-1 knock-down BCCs and increased exogenous SDF-1α prevented contact inhibition between BCCs and BM stroma. Contact inhibition was restored with low SDF-1α levels. Long-term culture-initiating assays with CD34+/CD38–/Lin– showed normal hematopoiesis provided that SDF-1α levels were reduced in BCCs. Gap junctions (connexin-43 [CX-43]) were formed between BCCs and BM stroma, with concomitant interaction between CD34+/CD38–/Lin– and BM stroma but not with the neighboring BCCs. In summary, SDF-1α levels are reduced in BCCs that contact BM stroma. The low levels of SDF-1α in BCCs regulate interactions between BM stroma and hematopoietic progenitors, consequently facilitating normal hematopoiesis.

scholarly journals Asiatic Acid Interferes with Invasion and Proliferation of Breast Cancer Cells by Inhibiting WAVE3 Activation through PI3K/AKT Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Xiao-jun Gou ◽  
Huan-huan Bai ◽  
Li-wei Liu ◽  
Hong-yu Chen ◽  
Qi Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Nude Mice ◽  
Breast Cancer Cells ◽  
Akt Signaling ◽  
Asiatic Acid ◽  
Akt Signaling Pathway ◽  
Xenografted Tumor

Objective. To explore the ability of asiatic acid to interfere with the invasion and proliferation of breast cancer cells by inhibiting WAVE3 expression and activation through the PI3K/AKT signaling pathway. Methods. The MDA-MB-231 cells with strong invasiveness were screened by transwell assay, and plasmids with high expression of WAVE3 were constructed for transfection. The transfection effect and protein expression level of plasmids were verified by PCR and WB. The effects of asiatic acid on cell proliferation and invasion were investigated by flow cytometry. The xenografted tumor models in nude mice were established to study the antitumor activity of asiatic acid. Results. Asiatic acid significantly inhibited the activity of MDA-MB-231 cells, and the expression level of WAVE3 increased significantly in the tissue of ductal carcinoma in situ and was lower than that in the metastasis group. After plasmid transfection, the mRNA and protein expression of WAVE3 increased significantly in the cells. Asiatic acid at different concentrations had an impact on cell apoptosis and invasion and could significantly inhibit the expression of WAVE3, P53, p-PI3K, p-AKT, and other proteins. The T/C(%) of asiatic acid (50 mg/kg) for MDA-MB-231(F10) xenografted tumor in nude mice was 46.33%, with a tumor inhibition rate of 59.55%. Asiatic acid could significantly inhibit the growth of MDA-MB-231 (F10) xenografted tumors in nude mice (p<0.05). Conclusions. Asiatic acid interferes with the ability of breast cancer cells to invade and proliferate by inhibiting WAVE3 expression and activation and the mechanism of action may be related to the PI3K/AKT signaling pathway.

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