Multiplex imaging in therapy refractory tumors: understanding the spatiotemporal facets of an immunosuppressive environment

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY In recent years, it appeared that the cancer treatment revolution had arrived: immunomodulatory therapies. Although these breakthroughs unleash the immune system and can be deadly to tumors, there are a high percentage of cancers that fail to respond. One complicating aspect is tumor heterogeneity, both within the same cancer type and within a single patient. This aspect is especially prominent in pancreatic adenocarcinoma (PDA), which is notoriously resistant to many frontline immunotherapies and has a low 5-year survival rate. Although mouse models have made research into PDA more accessible, these models frequently fail to capture the spectrum of tumor heterogeneity in human PDA. Innovation. To address this limitation, I will use a unique collection of mouse pancreatic tumor clones with distinct and reproducible responses to treatment, mimicking the tumor heterogeneity seen in the clinic. This will provide me with unparalleled comparative and combinatorial power to interrogate the tumor microenvironment. Additionally, my proposed experimental approach will leverage emerging high-content imaging methods that are able to reveal the phenotype, activity, and spatial organization of the tumor microenvironment in situ.

Public health relevance public domain (NIH RePORTER)

RELEVANCE: Pancreatic cancer is an aggressive and therapeutically difficult cancer to treat. Mouse models of pancreatic cancer are therefore paramount to our mechanistic understanding of tumor microenvironment dynamics and immunomodulatory interventions. The overall goal of this research is to use cutting-edge microscopy techniques to mechanistically understand the fine grain cellular interactions that dictate tumor responsiveness and leverage them to improve synergistic therapeutic strategies