During dissemination, metastatic (individual) cancer cells can modulate the morphodynamics of invasive protrusions to optimize their migration efficiency. It still remains unclear though how the stochastic fluctuations of protrusions regulate the invasion of more complex multi-cellular tumors, and how they correlate with their metastatic potential. Herein, we used a reductionist approach based on tumor cell micro-spheroids with increasing invasion capability to investigate the role of fluctuating protrusions in breast cancer progression. To quantitate protrusion fluctuations, we defined a set of key biophysical parameters that precisely correlated with the invasive potential of tumors. We showed that by perturbing protrusion activity using standard chemotherapeutics and pharmacological inhibitors of key signaling pathways, tumor invasiveness was significantly altered. Finally, we defined a novel quantitative index encoding a minimal set of biophysical parameters and the relative levels of cell-cell/ECM interactions, which was capable to assess tumor invasion capability. Overall, this work provides a new biophysical framework showing how protrusion fluctuations regulate tumor cell invasion, suggesting that they may be employed as an early indicator – signature – of the metastatic potential of tumors.