A Novel Inhibitor of Carbonic Anhydrases Prevents Hypoxia-Induced TNBC Cell Plasticity.

Annachiara Sarnella,Jean-Yves Winum,Giuseppina De Simone,Antonella Zannetti,Vincenzo Alterio,Claudiu T Supuran,Billy Samuel Hill,Giuliana D’Avino

doi:10.3390/ijms21218405

Abstract

Cell plasticity is the ability that cells have to modify their phenotype, adapting to the environment. Cancer progression is under the strict control of the the tumor microenvironment that strongly determines its success by regulating the behavioral changes of tumor cells. The cross-talk between cancer and stromal cells and the interactions with the extracellular matrix, hypoxia and acidosis contribute to trigger a new tumor cell identity and to enhance tumor heterogeneity and metastatic spread. In highly aggressive triple-negative breast cancer, tumor cells show a significant capability to change their phenotype under the pressure of the hypoxic microenvironment. In this study, we investigated whether targeting the hypoxia-induced protein carbonic anhydrase IX (CA IX) could reduce triple-negative breast cancer (TNBC) cell phenotypic switching involved in processes associated with poor prognosis such as vascular mimicry (VM) and cancer stem cells (CSCs). The treatment of two TNBC cell lines (BT-549 and MDA-MB-231) with a specific CA IX siRNA or with a novel inhibitor of carbonic anhydrases (RC44) severely impaired their ability to form a vascular-like network and mammospheres and reduced their metastatic potential. In addition, the RC44 inhibitor was able to hamper the signal pathways involved in triggering VM and CSC formation. These results demonstrate that targeting hypoxia-induced cell plasticity through CA IX inhibition could be a new opportunity to selectively reduce VM and CSCs, thus improving the efficiency of existing therapies in TNBC.

Highlights

The various components of the tumor microenvironment (TME) such as stromal cells, extracellular matrix (ECM), signaling molecules, low oxygen and acidic pH control tumor cell phenotypic switching which favors the onset of chemoresistance, immune evasion, cell invasion and metastasis [1]
We investigated whether targeting carbonic anhydrase IX (CA IX) with a novel benzoxaborole inhibitor, RC44 [22,23], which was reported to inhibit other carbonic anhydrase isoforms including CA I, CA II and CA XII, was possible to hamper the impact of hypoxia on Triple-negative breast cancer (TNBC) plasticity, reducing
We found that RC44 down-regulated β-catenin expression, a protein well known to be correlated with stemness and epithelial-to-mesenchymal transition (EMT), which has been reported to reduce cell adhesion interacting with CA IX [27]

Summary

Introduction

The various components of the tumor microenvironment (TME) such as stromal cells, extracellular matrix (ECM), signaling molecules, low oxygen and acidic pH control tumor cell phenotypic switching which favors the onset of chemoresistance, immune evasion, cell invasion and metastasis [1] This ability of tumor cells to change identity through non-mutational mechanisms to cope with TME pressure is known as tumor cell plasticity and is strictly associated with the intratumoral heterogeneity of many carcinomas, causing failure of anti-cancer therapies [2]. Through genetic profiles, TNBC was clustered into four main sub-types: Basal-like immunosuppressed (BLIS), basal-like immune activated (BLIA), mesenchymal (MES), and luminal androgen receptor (LAR) [6] These sub-groups are characterized by distinct molecular features and show different aggressive behavior and response to therapies [7]

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Discussion

Conclusion