Innovative preclinical platform to highlight the impact of macro and microenvironment on pancreatic cancer development and therapy response

The poor outcome of pancreatic adenocarcinoma (PDAC) is due to the lack of early biomarkers and therapeutic options. The impact of the systemic temporal and spatial activation response, defined as macroenvironment, on PDAC is not fully understood. Key questions remain about the timing and occurrence of early systemic responses. This knowledge gap is primarily due to the absence of human and animal models that can intercept early tumor-related systemic perturbation before tumor uptake. We have developed the MITO-Luc reporter mouse model to measure physiological and/or aberrant proliferation in any body district by non-invasive bioluminescence imaging. To design new therapeutic protocols< with precise timing, targeting systemic aberrant proliferation before tumor appearance, we crossed MITO-Luc mouse with PDAC models carrying oncogenic Kras alone (KC) or with mutant p53 (KPC) in pancreatic cells. This mice model allows for the non-invasive tracking of early and late stages of PDAC development in live animals. Taking advantage of this model, we have been able to intercept early systemic events in the hematopoietic organs occurring significantly before the appearance of pre-cancerous lesions and/or a palpable tumor. We also have results regarding the molecular and cellular critical players involved in the early steps of PDAC development. To generate a preclinical platforms to explore the efficacy of new combination therapies, targeting both PDAC cells and microenvironment, we inoculated cell lines with different ability to recruit microenvironment derived from KC and KPC mouse models into MITO-Luc mice. We found a different immune cells and CAFs recruitment in tumors that recruit lower or higher number of proliferating endogenous cells. Furthermore, taking advantage of tumor slice cultures reflecting the state of tumor behavior and heterogeneity, we highlighted a simple approach to study cancers with intact microenvironment. We observed that, upon 72 hours of culture, PDAC, stromal and immunological cells are present and still alive.