Lung cancer is the leading cause of cancer-related deaths, and risks are disproportionately high in veterans. Lung adenocarcinoma (LUAD) accounts for half of all lung cancer cases, but effective treatments are lacking in part due to an incomplete understanding of LUAD biology. LUAD tumors originate from airway secretory epithelia, and mucin expression is prevalent and associated with LUAD aggressiveness. However, mechanisms by which mucins affect LUAD pathogenesis are poorly understood. The overarching concept of this proposal is that aberrant epithelial growth in LUAD is potentiated by two polymeric mucins--MUC5AC and MUC5B. Though required for airway defense in health, MUC5AC and MUC5B misexpression in LUAD correlates with invasiveness, recurrence, and mortality, especially in patients with activating mutations in KRAS--the most common oncogenic driver of LUAD. We validated MUC5AC causatively in urethane and activated-Kras expression mouse models of LUAD. In animals lacking Muc5ac (‘MUC in humans, ‘Muc’ in mice), tumor number and size decreased by ~50%. The relative tumor-promoting effects of Muc5b on its own or with Muc5ac are not yet known. We seek to close this significance gap here. We also seek to determine molecular mechanisms for polymeric mucin-mediated tumor promotion. Studies by us and by others have identified numerous signals that stimulate LUAD, including mucinous LUAD subtypes. Upstream signaling pathways converge on mucins and their biosynthetic machinery. Individual MUC5AC and MUC5B molecules are extraordinarily large. They multimerize, and they become even more massive through addition of sugars to their central glycosylation domains. Accordingly, protein homeostasis (proteostasis) is tightly regulated during polymeric mucin biosynthesis. Mucin translation, folding, and dimerization occur in the endoplasmic reticulum (ER) and involve formation of hundreds of disulfide bonds. To handle these demands, mammals express a mucous cell specific isoform of the ER stress sensor inositol-requiring enzyme-1 (IRE-1, also called ER-to- nucleus signaling protein, or ERN). ERN1 is ubiquitously expressed and is crucial for ER stress-triggered apoptosis, but an isoform called ERN2 is restricted to mucous cells where it is required for sustaining mucin synthesis despite high levels of ER stress. This adaptation is accomplished by direct binding of ERN2 to ERN1 and subsequent suppression of ERN1-mediated pro-apoptotic signaling. While beneficial for host defense in health, apoptosis suppression could be detrimental in LUAD. We hypothesize that MUC5AC and MUC5B promote epithelial cell growth in LUAD via ERN2-dependent suppression of ER stress-induced apoptosis. The following three Specific Aims are proposed: 1) Test the hypothesis that MUC5AC/Muc5ac and MUC5B/Muc5b promote LUAD and mucinous LUAD; 2) Test the hypothesis that polymeric mucin expression in tumor cells promotes LUAD via ERN2/Ern2 dependent proteostasis dysfunction; 3) Test the hypothe...