Tumor evolution in an ecological context: How genetic and microenvironmental factors shape the pathogenesis of...

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis and a growing global incidence. Despite its clinical relevance, the processes driving PDAC tumorigenesis and progression remain poorly understood, challenging traditional molecular models. Here, we address the biological and evolutionary mechanisms underpinning PDAC development and growth, integrating cellular and molecular aspects with an ecological perspective. This multidisciplinary approach offers broader insights into the analysis of PDAC pathogenesis, starting from precancerous lesions and moving through to the primary tumor and its metastatic spread. Indeed, cancer cells may be considered as existing within a dynamic ecological context and are influenced by evolutionary pressures similarly to individuals, populations, and species in nature. Genetic and epigenetic changes form the foundation for the emergence of intratumoral heterogeneity, which contributes to tumor progression, metastasis, and resistance to therapy. These processes in PDAC progression are governed by both clonal expansion and the ecological fitness of neoplastic cells within the tumor microenvironment, which represents their ecological niches. Hence, by integrating evolutionary principles into the study of PDAC, we have analyzed the conceptual advantages and potential applications of this approach on the understanding of the complex interactions between tumor cells and their environments. This research emphasizes the contribution of a holistic, evolutionary perspective to cancer biology and underlines the importance of considering genetic, cellular, and ecological factors in the management and development of treatments, and for guiding future research and therapeutic strategies.