EVALUATING THE ROLE OF TUMOR MICROENVIRONMENT HETEROGENEITY IN THE PROGRESSION AND TREATMENT RESISTANCE OF PANCREATIC DUCTAL ADENOCARCINOMA

Abstract

Pancreatic ductal adenocarcinoma is a cancer that still poses one of the most deadly malignancies with a complicated and heterogeneous tumor microenvironment that has contributed to the universal resistance to treatment. In this study, a multi-dimensional, problem-oriented methodology was utilized that combines high-dimensional spatial proteomics, microfluidic organotypic systems, measurements of therapeutic recalcitrance in tumor microenvironment metabolic flux and computer modeling of agents to comprehend the mechanistic nature of therapeutic recalcitrance in tumor microenvironment. We demonstrated by multiplex immunohistochemistry and imaging mass cytometry of untreated and treated samples of patients that the canonical chemotherapy induces a so much remodelling of spatial distributions that both inflammatory cancer-associated fibroblasts and M2 macrophages become more colocalized by 76 percent and The crosstalk of Single-cell metabolic profiling revealed a functional dichotomy with inflammatory cancer-associated fibroblasts having high glycolytic and glutaminolytic flux and myofibroblastic cancer-associated fibroblasts specialising in collagen synthesis. Goal-oriented agent-based computational modeling found that combination therapy based on triple combination therapy that included extracellular matrix degradation, transforming growth factor-beta inhibition and chemotherapy, led to a higher likelihood of tumor control of nearly 90 percent as compared to monotherapies with less than 15 percent success. M2 to M1 macrophage ratio was found to be the most critical negative prognostic of overall survival, as well as the tissue stiffness and effective drug diffusivity. In other words, this concerted study confirms that pancreatic ductal adenocarcinoma therapeutic resistance is the concerted action of physical, cellular, immunological and metabolic defenses that have to be rationally designed combination strategies that act in concert to destroy these interrelationships of defenses to produce a long-term clinical response.