Matrix metalloproteinase 9 (MMP9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP9 and investigated the effects of specific long-term loss-of-function, by genetic ablation, of MMP9 on PDAC initiation and progression in the well-established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and immunohistochemistry. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization and zymography. PDAC tumors from MMP9-deficient mice were dramatically larger, more invasive and contained more stroma. Yet, ablation of MMP9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP9 led to increased IL-6 levels resulting from abrogation of MMP9-dependent SCF-signaling in the bone marrow (BM). IL-6 levels in MMP9-/- mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL-6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP9-deficient hosts. In conclusion, ablation of systemic MMP9 initiated fatal communication between maintenance of physiological functions of MMP9 in the BM and invasive growth of PDAC via the IL-6/IL6R/STAT3 axis. Implications: Thus, the beneficial effects of host MMP9 on PDAC are an important caveat for the use of systemic MMP9 inhibitors in cancer.