Chemotherapy is the most common therapeutic option for metastatic breast cancer, but resistance readily arises. The link between metastasis and chemoresistance remains poorly understood. A recent report (Cell 150, 165–178) uncovers a signaling network linking metastatic and chemoresistant behavior and expands our understanding of the emerging role of the tumor microenvironment in controlling therapy responses.

Studying two related proteins previously associated with metastasis, CXCL1 and CXCL2 (CXCL1/2), Acharyya et al. find that they play a prometastatic part in cancer through their paracrine action on myeloid cells. Moreover, CXCL1/2-recruited myeloid cells can secrete factors that promote not only growth and metastasis but also the survival of cancer cells after chemotherapy.

Interestingly, the production of CXCL1/2 is upregulated in tumor cells treated with chemotherapy drugs. This stems from the proinflammatory effect of such therapies on normal tissues, leading stromal components to release cytokines that can upregulate the expression of CXCL1/2.

The authors find evidence that this signaling loop operates in humans with metastatic breast cancer and suggest that it may be a future target to prevent microenvironmental components from creating a protective milieu that allows the acquisition of therapy resistance.