Metastasis of tumor cells to distant organs is the leading cause of mortality from cancer. While cancer cell migration has been extensively studied in 2D, there is still insufficient understanding of the different modes of cancer invasion and their molecular underpinnings in physiologically relevant 3D environments. This is of particular importance for developing more efficient anti-metastatic therapies since the existence of alternative migratory modes enables tumor cells to show resistance towards treatments that may selectively inhibit a single migratory mode.Here, we use highly aggressive breast adenocarcinoma cells depicting round morphology either as a constitutive intrinsic property or as a cellular response induced by specific ECM conditions to delineate the molecular underpinnings of a novel alternative mode of round cancer invasion in 3D environments. We have identified a novel invasion mode in which rounded, bleb-bearing cells demonstrate extensive force generation and ECM re-organization, a mode distinct from those that have been previously described. Analysis of bleb-mediated tumor spheroid invasion under pharmacological inhibition of various migration-associated cellular pathways demonstrated that this novel migratory mode relies on cell contractility but is also integrin- and protease-dependent, in contrast to classical amoeboid migration. Using confocal reflectance microscopy of spheroids invading 3D collagen matrices, we demonstrate that bleb-bearing cells re-organize the ECM in a highly efficient manner and that blebs are specific sites of collagen fiber attachment and force generation. Using high resolution multicolor confocal microscopy of 3D-embedded cancer cells we show for the first time that blebs of invading cancer cells are sites of integrin accumulation at the bleb neck region and contribute directly to the re-organization of the ECM. Moreover, these sites show an accumulation of activated integrin receptors and strong co-localization with cholesterol-rich membrane microdomains, indicating that the bleb neck is a hotspot of locomotion-related signaling machinery. This is in contrast to the classical view of the bleb as merely pushing back the immediate cell environment and reveals a new function of blebby protrusions in 3D cancer cell locomotion. Taken together, we describe a novel bleb-mediated 3D migratory mode of cancer cells and its molecular characteristics in physiologically relevant 3D environments and demonstrate for the first time a novel function of blebs in 3D cancer cell invasion.