Pancreatic ductal adenocarcinoma (PDA) incidence is rising. Pancreatic intraepithelial neoplasms (PanINs) are PDA precursors that are common in asymptomatic adults, but only few progress to PDA. The critical regulators of PanIN progression to PDA and metastases remain unknown. KRAS mutations occur in > 92% of human low- grade PanINs. Pancreatic KrasG12D mutation (mKRAS) in mice (KC mice) induces PanINs that mimic human low- grade PanINs but fail to progress to PDA. High fat diet (HFD) and pancreatic P53 mutations (e.g., KPC mice) promote a pancreatic immunosuppressive tumor microenvironment (iTME) and PanIN progression to PDA and metastases in KC mice. Dietary fatty acids are natural activating ligands of peroxisome proliferator-activated receptor-delta/beta (PPARD). PPARD is upregulated in human PDA, but its role in PDA is understudied. We have found 1) PPARD was upregulated in human and KC mice PanINs; 2) Pancreatic PPARD knockout (KO) in KC mice suppressed HFD promotion of PanIN progression to PDA; 3) PPARD activation by a HFD diet or diet containing GW501516, a synthetic PPARD ligand (GW diet), accelerated PanIN progression to PDA in KC mice, and to a greater extent, in KC/Pd mice with PPARD overexpression in pancreatic mKRAS+ cells; 4) PPARD induced pancreatic epithelial cells to produce chemokines and cytokines (e.g. CCL2, IL-6, GM-CSF) that recruited immunosuppressive cells to form an iTME; 5) PPARD KO in KPC cells (KPC-PdKO) suppressed PDA and metastases while pancreatic PPARD overexpression in KPC mice (KPC/Pd) fed HFD promoted metastases; and 6) PPARD and platelet derived growth factor receptor beta (PDGFRb) expression levels were correlated in human PDA. iTME activates PDGFRb in PDA cells to promote metastasis. We thus hypothesize that activation of upregulated PPARD in mKRAS+ pancreatic epithelial cells induces and sustains an iTME to promote PDA progression and metastasis. Aim 1 will determine 1) whether activation of upregulated PPARD in pancreatic mKRAS+ cells by a GW diet is sufficient to maintain an iTME and promote PDA progression in KPC/Pd mice and KC/PD-i-fElasCreERT mice (Subaim 1a), in KPC cells with and without PDGFRb KO orthotopically injected into syngeneic immunocompetent mice (B6.129S) and immunodeficient NSG mice (Subaim 1b), and in human PanIN–derived organoids (PanIN-DO) transduced with Tet-on inducible PPARD expression lentivirus and orthotopically transplanted into NSG mice with (HuCD34-NSG) and without (NSG) humanized immune systems (Subaim 1c); and 2) the chemokines and cytokines, as well as their cell origins, that PPARD employs to maintain pancreatic iTME using CITE-seq (Subaim 1d). Aim 2 will determine the effects of pancreatic PPARD KO on the pancreatic iTME and PDA progression in KC/PdKO-fElasCreERT mice fed a HFD and in syngeneic and NSG mice orthotopically injected with KPC-PdKO cells and fed a GW diet (Subaim 2a), as well as in HuCD34-NSG and NSG mice transplanted with human PDA-derived organoids without ...