Journal of Cancer Stem Cell Research

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N-cadherin/Connexin43 Axis Is Critical to Maintain Breast Cancer Stem Cells: Implication for Cancer Dormancy in Bone Marrow

Journal of Cancer Stem Cell Research

Abstract

Clinical advancement in the field of breast cancer (BC) has given access to better diagnosis and treatment. Despite
these advancements,BCrelapse remains a clinical problem. The clinical and research evidence have mainly attributedBCrelapse
to dormantBCcells (BCCs) in bone marrow, (BM). Research from our lab and others have shown that the dormantBCCswithin the
BM niche are cancer stem cells (CSCs). The CSCs interact with the resident BM cells such as macrophages, fibroblasts and
mesenchymal stem cells (MSCs), via cytokines, exosomes and/or connexin mediated gap junction intercellular communication
(GJIC). This study focuses on GJIC. Connexin 43 (Cx43) has been demonstrated to be involved in GJIC between CSCs and BM
supporting cells. Since Cx43 is also important for hematopoiesis, this particular molecule could not be a druggable target to
reverse the dormant phase of BCC. We therefore seek for additional target to disrupt GJIC in order for the CSCs to become
chemosensitive. This study tested the hypothesis that low level of N-cadherin, an epithelial to mesenchymal transition (EMT)
protein, is required for Cx43-mediated GJIC. Knockdown of N-cadherin significantly reduced GJIC, based on dye transfer
between CSCs and BM stromal cells. Furthermore, N-cadherin knockdown appeared to induce the differentiation of CSCs as
demonstrated by decrease expression of stem cell-associated genes and reduced ability of serial passaging of spheroids.
Evidence of direct interaction between N-cadherin and Cx43 was shown by single cell imaging with the Amnis, flow-cytometry,
and immunoprecipitation. Cytokines such as TGFb and CXCL12 regulate the expression of N-cadherin. In vivo studies using a
model ofBCdormancy indicated that the dormantCSCs was significant reduced in theBMfollowing knockdown of N-cadherin or
Cx43. In summary, the molecular interaction between N-cadherin and Cx43 seems to be critical in sustaining dormancy of CSCs
in BM. The results have implications to reverse BC dormancy for precise targeting.

  • Garima Sinha, Alejandra Ferrer, Seda Ghazarayan, Peter Conaty, Bernadette M. Bibber1, Ponzio M. Nicholas, and Pranela Rameshwa
  • Journal of Cancer Stem Cell Research 2019, 6:e1006 (January 07, 2019)
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  • DOI: 10.14343/JCSCR.2018.6e1006

Editors-In-Chief

Pranela Rameshwar, Ph.D.
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Mariusz Ratajczak, M.D., Ph.D. ...
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Justin Lathia, Ph.D.
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