A RECENT study has unveiled a mechanism by which estrogen receptor-positive (ER+) breast cancer cells become more aggressive after spreading to the bone marrow. The research highlights the role of direct contact between cancer cells and mesenchymal stromal cells (MSCs) in the bone marrow, facilitated by CX43-related tunneling nanotubes.
In the bone marrow microenvironment, ER+ breast cancer cells interact closely with MSCs. To model these interactions, researchers co-cultured tumor cells with MSCs and employed integrated transcriptome-proteome-network analyses. They discovered that direct contact between cancer cells and MSCs led to significant changes in gene and protein expression within the tumor cells, changes not replicated when cancer cells were exposed solely to MSC-conditioned media. This suggests that physical contact is crucial for the observed phenotypic transformations.
A key finding was the identification of the protein CCDC88A, also known as GIV, which is associated with metastasis and growth signaling autonomy. Although ER+ breast cancer cells typically lack GIV, the study found that MSCs transfer this protein to cancer cells through tunneling nanotubes mediated by connexin 43 (CX43). This transfer appears to endow the cancer cells with more aggressive characteristics.
When GIV was introduced into GIV-negative breast cancer cells, approximately 20% of the gene expression changes observed in direct co-cultures were reproduced. These GIV-expressing cells exhibited increased resistance to anti-estrogen drugs and enhanced metastatic potential. This underscores the role of GIV in promoting tumor aggressiveness and therapy resistance.
The study provides a comprehensive multi-omic insight into the intercellular transport mechanisms between MSCs and tumor cells. It validates how the transfer of proteins like GIV from MSCs to ER+ breast cancer cells can orchestrate more aggressive disease states. These findings open potential avenues for therapeutic interventions targeting the tumor microenvironment and intercellular communication pathways to mitigate breast cancer progression.
Reference: Sinha S et al. Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels. J Clin Invest. 2024;134(24):e170953.
Anaya Malik | AMJ
