Project Summary / Abstract
Pancreatic ductal adenocarcinoma (PDA) is a devastating disease lacking effective treatment options. PDA is
characterized by a dense and fibrotic tumor microenvironment deposited by extensive and diverse fibroblast
and immune cell populations within this niche. The diversity of cell types within PDA tumors also extends to
cancer cells themselves, as heterogenous subpopulations of cancer cells are capable of symbiotic behaviors
that support resistance to therapy. Accordingly, targeting crosstalk interactions can remove barriers to allow
more effective clinical treatment. Investigating clonal PDA behaviors, we have identified two metabolic
subpopulations differentiated by their sensitivity to mitochondrial inhibition. Metabolic exchange between these
populations confers resistance mediated by asparagine that is overproduced and released through a
constitutively active integrated stress response in the insensitive clones. Further, we observed that degradation
of asparagine functions to sensitize PDA to mitochondrial inhibitors. Targeting mitochondrial metabolism in
PDA cells functions to lower intercellular nucleotide pools that compete with standard of care chemotherapy,
pyrimidine anti-metabolites. Further, targeting mitochondrial metabolism also functions to reduce the anti-
inflammatory polarization of tumor-associated macrophages that provide non-cell autonomous
chemoresistance. This research proposal will target factors underpinning the programming of PDA cells that
produce and release asparagine (Aim 1). We have identified oncogenic and stress pathways that can be
targeted to impair the survival of asparagine producing cells and disrupt metabolic crosstalk. Further, we have
identified that asparagine producing PDA cells have hypermethylated histones that correlate with a
mesenchymal state. Accordingly, we will leverage metabolic approaches to normalize the histone methylation
and reprogram these cells to desensitize them to mitochondrial inhibition. In parallel, we will combine treatment
of mitochondrial inhibitors potentiated through asparagine degradation and with standard of care
chemotherapy (Aim 2). Both systemic and local asparagine levels will be targeted and compared for efficacy in
enhancing mitochondrial inhibitors. These experiments will be performed in multiple human and murine tumor
models, and analyzed through a combination of techniques that will allow for in vivo assessment of PDA
metabolic subtype response to therapy. Finally, we will characterize the remodeling of the immune and stromal
compartments of PDA tumors in response to mitochondrial inhibitors potentiated by asparagine degradation to
identify new immune targeting approaches. Together, these data will provide important insights into
mechanisms that maintain cancer cell heterogeneity and generate important pre-clinical data examining the
impact of targeting metabolic crosstalk pathways to enhance PDA response to therapy.