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. Induced genes and proteins in cancer cells, some borrowed and others tumor-intrinsic, were not recapitulated merely by conditioned media from MSCs. Protein-protein interaction networks revealed the rich connectome between ′borrowed′ and ′intrinsic′ components. Bioinformatic approaches prioritized one of the ′borrowed′ components, CCDC88A/GIV, a multi-modular metastasis-related protein which has recently been implicated in driving one of the hallmarks of cancers, i.e., 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 ~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.