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. 2024 Mar 1;17(3):dmm050542.
doi: 10.1242/dmm.050542. Epub 2024 Mar 20.

Stress in the metastatic journey - the role of cell communication and clustering in breast cancer progression and treatment resistance

Eloïse M Grasset  1   2 , Sophie Barillé-Nion  1   2 , Philippe P Juin  1   2   3
Affiliations

Stress in the metastatic journey - the role of cell communication and clustering in breast cancer progression and treatment resistance

Eloïse M Grasset et al. Dis Model Mech. .

Abstract

Breast cancer stands as the most prevalent malignancy afflicting women. Despite significant advancements in its diagnosis and treatment, breast cancer metastasis continues to be a leading cause of mortality among women. To metastasize, cancer cells face numerous challenges: breaking away from the primary tumor, surviving in the circulation, establishing in a distant location, evading immune detection and, finally, thriving to initiate a new tumor. Each of these sequential steps requires cancer cells to adapt to a myriad of stressors and develop survival mechanisms. In addition, most patients with breast cancer undergo surgical removal of their primary tumor and have various therapeutic interventions designed to eradicate cancer cells. Despite this plethora of attacks and stresses, certain cancer cells not only manage to persist but also proliferate robustly, giving rise to substantial tumors that frequently culminate in the patient's demise. To enhance patient outcomes, there is an imperative need for a deeper understanding of the molecular and cellular mechanisms that empower cancer cells to not only survive but also expand. Herein, we delve into the intrinsic stresses that cancer cells encounter throughout the metastatic journey and the additional stresses induced by therapeutic interventions. We focus on elucidating the remarkable strategies adopted by cancer cells, such as cell-cell clustering and intricate cell-cell communication mechanisms, to ensure their survival.

Keywords: Breast cancer; Cluster; Metastasis; Stress.

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Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Cancer cell stresses during the metastatic cascade. Cancer cells are exposed to numerous stresses they need to counteract to survive and form distant metastasis. The main physiological stresses inherent to cancer development are indicated for each of the distinct steps of the metastatic cascade. Therapy-induced stresses also have effects throughout these steps and include chemotherapies, surgery, radiotherapies and immunotherapies. NETosis, release of neutrophil extracellular traps (NETs).
Fig. 2.
Fig. 2.
Stress in the circulation – united we stand, divided we fall. (A) Single circulating tumor cells (CTCs) often die by anoikis or ferroptosis, or are eliminated via immune surveillance. NK cells, natural killer cells; ROS, reactive oxygen species. (B) However, CTCs can form homotypic (cancer cells only) or heterotypic (cancer and non-cancer cells) clusters to enhance their survival in circulation. Homotypic CTC clusters preserve cell–cell contacts through a variety of complexes, including plakoglobin, homophilic CD44 interaction, E-cadherin and nectin-4. The distinct types of heterotypic CTC clusters observed in patient are also shown. CTC clusters survive in circulation by different mechanisms, including a decrease in internal ROS, inhibition of ferroptosis, increase in the expression of ‘stemness’ genes, increase in the expression of genes implicated in proliferation and a decrease in NK cell recognition.
Fig. 3.
Fig. 3.
Disseminated cancer cells and metastasis formation. (A) Most single disseminated tumor cells (DTCs) die within hours after extravasating into a new tissue due to an inhospitable environment and immune clearance. DTCs that survive this first step of colonization can either proliferate or enter dormancy, notably to avoid immune recognition. Multiple factors secreted by the host organ or cancer cells themselves promote dormancy and survival of dormant DTCs. Although the mechanisms implicated in the awakening of dormant DTCs are not fully understood, it has been shown that inflammation promotes dormant DTC proliferation due to neutrophil activation and the production of neutrophil extracellular traps (NETs), a process known as NETosis. Other mechanisms implicated are fibrosis and aging, notably with the production of the Wnt ligand sFRP1 by aged fibroblasts. (B) Unlike single DTCs, DTC clusters have been shown to colonize distant sites more efficiently and to resist apoptosis upon extravasation, notably due to their ability to form nanolumens in which the cancer cells secrete epigen, and due to the initiation of epigenetic reprogramming promoting the expression of stemness and proliferation genes. Bone marrow-derived mesenchymal stromal cells can also induce pro-tumorigenic and pro-metastatic neutrophils that promote macrometastatic outgrowth. Although it is not clear yet whether DTCs clusters can enter dormancy, the multiclonality of these clusters can offer a survival and proliferation advantage.
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References

    1. Aceto, N., Bardia, A., Miyamoto, D. T., Donaldson, M. C., Wittner, B. S., Spencer, J. A., Yu, M., Pely, A., Engstrom, A., Zhu, H.et al. (2014). Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110-1122. 10.1016/j.cell.2014.07.013 - DOI - PMC - PubMed
    1. Albrengues, J., Bourget, I., Pons, C., Butet, V., Hofman, P., Tartare-Deckert, S., Feral, C. C., Meneguzzi, G. and Gaggioli, C. (2014). LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep. 7, 1664-1678. 10.1016/j.celrep.2014.04.036 - DOI - PubMed
    1. Albrengues, J., Bertero, T., Grasset, E., Bonan, S., Maiel, M., Bourget, I., Philippe, C., Herraiz Serrano, C., Benamar, S., Croce, O.et al. (2015). Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204. 10.1038/ncomms10204 - DOI - PMC - PubMed
    1. Albrengues, J., Shields, M. A., Ng, D., Park, C. G., Ambrico, A., Poindexter, M. E., Upadhyay, P., Uyeminami, D. L., Pommier, A., Küttner, V.et al. (2018). Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227. 10.1126/science.aao4227 - DOI - PMC - PubMed
    1. Allen, T. A., Asad, D., Amu, E., Hensley, M. T., Cores, J., Vandergriff, A., Tang, J., Dinh, P.-U., Shen, D., Qiao, L.et al. (2019). Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential. J. Cell Sci. 132, jcs231563. 10.1242/jcs.231563 - DOI - PMC - PubMed
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