Project 2: Targeting signaling networks to overcome therapeutic resistance in pancreatic cancer

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PROJECT SUMMARY – Project 2: Signaling Pancreatic ductal adenocarcinoma (PDA) is most commonly diagnosed at late stages, at which time the disease is refractory to most conventional treatment options. Identifying therapeutic strategies that pre-empt the development of resistance and achieve durable tumor control has been hampered by the enormous complexity of the paracrine signaling network in PDA. STAT3 is a major node in this resistance network. The Hunter lab has shown that production of leukemia inhibitory factor (LIF) by cancer associated fibroblasts (CAFs) is a major driver of STAT3 signaling in tumor cells and promotes chemoresistance. Further, they have shown that LIF and the related cytokines IL6 and OSM may also play a role in STAT3 signaling in the immune microenvironment (IME). In Aim 1, the team will investigate the extent to which induction of STAT3 signaling by these cytokines contributes to tumor growth and therapeutic resistance. High-resolution spatial profiling and single-cell approaches will be used to delineate the cell type-specific alterations in STAT3 activation using syngeneic orthotopic models of PDA following treatment with chemotherapy and blockade of LIF, IL6, and/or OSM, which will be corroborated with the colocalization of cytokines and STAT3 signaling in human patient specimens. As LIF can activate several pro-survival pathways, the importance of STAT3-dependent and -independent mechanisms to PDA growth and chemoresistance will be determined. In addition to chemotherapy, the ability of cytokine blockade to potentiate immune checkpoint inhibition (ICI) will be investigated. Further, the team has discovered that aberrant glycosylation can also modulate the STAT3 pathway. Elevation of the glycan CA19-9 in organoids and in vivo resulted in increased STAT3 signaling in both the epithelial and stromal compartments. In Aim 2, the mechanism by which CA19-9 elevation activates STAT3 will be determined and the role of this signaling pathway in chemoresistance will be dissected in a cell type-specific manner using a novel organoid co-culture platform and a first of its kind genetically engineered mouse model with pancreas-specific KRAS and TRP53 mutations and inducible CA19-9 expression. In addition to STAT3, CA19-9 elevation promotes receptor tyrosine kinase signaling, including activation of the EGFR pathway, which also drives chemoresistance. However, inhibition of either pathway has yielded limited clinical success. The team’s preliminary studies have revealed correlations between elevated CA19-9, resistance to chemotherapy, and induction of autophagy, a pathway known to mediate resistance to both chemotherapeutics and targeted therapies. Therefore, experiments proposed in Aim 3 will systematically dissect how CA19-9 modulation of STAT3, EGFR, and autophagy contribute to therapeutic resistance. It is important to note that most previous mouse studies on these resistance pathways have been performed in the absence of CA19-9 and that >90% of PDA patients are CA19-9 positive. Advanced organoid methodologies will be used to investigate both genetic and pharmacologic perturbation of these pathways, culminating in in vivo explorations of the efficacies of combination treatment strategies in CA19-9-positive PDA.