Acquisition of CCDC88A/GIV through Tumor-Stroma Tunnels Promotes Aggressive Phenotypes of Estrogen Receptor-Positive Breast Cancer [dataset3]

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 using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.