Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels

Saptarshi Sinha; Brennan W. Callow; Alex P. Farfel; Suchismita Roy; Siyi Chen; Maria Masotti; Shrila Rajendran; Johanna M. Buschhaus; Celia R. Espinoza; Kathryn E. Luker; Pradipta Ghosh; Gary D. Luker

doi:10.1172/JCI170953

Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels

Saptarshi Sinha,¹ Brennan W. Callow,² Alex P. Farfel,² Suchismita Roy,¹ Siyi Chen,² Maria Masotti,³ Shrila Rajendran,² Johanna M. Buschhaus,² Celia R. Espinoza,¹ Kathryn E. Luker,² Pradipta Ghosh,¹ and Gary D. Luker²

Published October 31, 2024 - More info

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Abstract

Estrogen receptor-positive (ER⁺) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between ‘borrowed’ and ‘intrinsic’ components. Bioinformatics prioritized one of the ‘borrowed’ components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER⁺ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER⁺ breast cancer) orchestrates aggressive disease states.

Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels

Saptarshi Sinha,¹ Brennan W. Callow,² Alex P. Farfel,² Suchismita Roy,¹ Siyi Chen,² Maria Masotti,³ Shrila Rajendran,² Johanna M. Buschhaus,² Celia R. Espinoza,¹ Kathryn E. Luker,² Pradipta Ghosh,¹ and Gary D. Luker²

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Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels

Saptarshi Sinha,1 Brennan W. Callow,2 Alex P. Farfel,2 Suchismita Roy,1 Siyi Chen,2 Maria Masotti,3 Shrila Rajendran,2 Johanna M. Buschhaus,2 Celia R. Espinoza,1 Kathryn E. Luker,2 Pradipta Ghosh,1 and Gary D. Luker2

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Saptarshi Sinha,¹ Brennan W. Callow,² Alex P. Farfel,² Suchismita Roy,¹ Siyi Chen,² Maria Masotti,³ Shrila Rajendran,² Johanna M. Buschhaus,² Celia R. Espinoza,¹ Kathryn E. Luker,² Pradipta Ghosh,¹ and Gary D. Luker²