In this issue of the Journal, Schmid et al identify Spondin 2 (SPON2) as a prominent downstream signaling target of metastasis-associated in colon cancer 1 (MACC1) in colorectal cancer (CRC). It is shown that SPON2 mediates MACC1-induced CRC cell proliferation, invasion and metastasis in vitro and in vivo, while its high expression correlates with adverse disease free survival in clinical samples. Therefore, not only does this study shed further light into the complexity of colorectal carcinogenesis, but it also puts forward a potential novel prognostic biomarker to predict high-risk tumors before they metastasize. The MACC1/SPON2 axis may also have utility beyond an indicator of tumor aggressiveness and lends itself as a promising therapeutic target for colorectal and potentially other solid tumors.