The long-term objective of this research proposal is to identify the mechanisms that induce metastatic dormancy and their subsequent chemo-resistance. Specific Aims: (1) To determine the functional contribution of PERK-dependent signaling pathways to p38-dependent induction of tumor dormancy in vivo; (2) To identify the molecular mechanisms that couple upregulation of BiP and activation of PERK to survival and drug resistance of dormant carcinoma cells. Tumorigenic (T-HEp3) and dormant (D-HEp3) cell-lines derived from HEp3 human squamous carcinoma will be used in chicken embryo chorioallantoic membrane (CAM) and nude mouse in vivo model systems. Stable and transient expression systems will be used to specifically modulate the PERK signaling and BiP expression, to determine if this pathway induces or interrupts dormancy and drug resistance in T- and D-HEp3 cells respectively. These studies will contribute to (1) understanding the mechanisms that regulate cancer dormancy and drug-resistance and (2) combine novel drugs that inhibit dormant tumor cell survival with conventional chemotherapeutics to eradicate residual cancer disease.