Specific N-cadherin-dependent pathways drive human breast cancer dormancy in bone marrow.

Garima Sinha,Pranela Rameshwar,Alejandra I Ferrer,Seda Ayer,Rakesh Kumar,Jie-Gen Jiang,Pradeep Barak,Bernadette M Bibber,Oleta A Sandiford,Yahaira Naaldijk,Sri Harika Pamarthi,Margarette Bryan,Nicholas M Ponzio,Ghassan Yehia,Jean-Pierre Etchegaray,Steven J Greco,Markos H El-Far

doi:10.26508/lsa.202000969

Abstract

The challenge for treating breast cancer (BC) is partly due to long-term dormancy driven by cancer stem cells (CSCs) capable of evading immune response and resist chemotherapy. BC cells show preference for the BM, resulting in poor prognosis. CSCs use connexin 43 (Cx43) to form gap junctional intercellular communication with BM niche cells, fibroblasts, and mesenchymal stem cells (MSCs). However, Cx43 is an unlikely target to reverse BC dormancy because of its role as a hematopoietic regulator. We found N-cadherin (CDH2) and its associated pathways as potential drug targets. CDH2, highly expressed in CSCs, interacts intracellularly with Cx43, colocalizes with Cx43 in BC cells within BM biopsies of patients, and is required for Cx43-mediated gap junctional intercellular communication with BM niche cells. Notably, CDH2 and anti-apoptotic pathways maintained BC dormancy. We thereby propose these pathways as potential pharmacological targets to prevent dormancy and chemosensitize resistant CSCs.

Highlights

Breast cancer (BC) remains a clinical problem despite the development of new drugs, improved screenings, and early intervention (Berry, 2013; Miller et al, 2016)
Given that connexin 43 (Cx43) expression was highest in cancer stem cells (CSCs) and such cells are difficult to eradicate, this study investigated the associated mechanism in Cx43-mediated gap junctional intercellular communication (GJIC) between CSCs and BM niche cells to maintain BC dormancy
The major question posed in this study is to determine the mechanisms of BC dormancy, pathways involved in GJIC between CSCs and BM niche cells (Patel et al, 2012)

Summary

Introduction

Breast cancer (BC) remains a clinical problem despite the development of new drugs, improved screenings, and early intervention (Berry, 2013; Miller et al, 2016). One of the major challenges is the ability of BC cells (BCCs) to survive for decades in a dormant state Such a state enables the BCCs to exist in cycling quiescence, which supports immune evasion and resistance towards therapy (Braun et al, 2005, 2009; Gelao et al, 2013; Mao et al, 2014; Massague & Obenauf, 2016; Otvos et al, 2016; Tjensvoll et al, 2019). MSCs, which constitute the cellular niche within the BM, can induce BCC quiescence through gap junctional intercellular communication (GJIC) and, through their exosomal secretome (Patel et al, 2014; Bliss et al, 2016; Sandiford et al, 2021)

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Results

Conclusion