S05-01 Mechanical cues shaping tumor progression and their relevance for pathways of chemical carcinogenesis

Abstract

Mechanical cues can be seen as an essential part of the tumor microenvironment: these include changes in tissue architecture upon tumor growth, shear stress experienced by the metastatic cells in the bloodstream or the interaction with the extracellular matrix (ECM) and its physiological stiffness. To support the necessary plasticity, cells can efficiently convert physical stimuli into biochemical signals via mechanotransduction. On these premises, the integration of physical cues into cell culture models (e.g. for the development of organ-on-chip platforms or microfluidic devices) not only contributes to the recreation of in vitro models that more faithfully reproduce cellular environment, but also opens up the possibility of novel signaling crossroads. Hypothesizing that physical forces could lever the same molecular targets as those modulated by the xenobiotics, it is possible to postulate that the final cellular response could reflect both contributions, similarly to chemical-mixture toxicology. Pursuing these ambitious questions, ovarian cancer cell models were chosen here to explore these delicate interactions. In addition to being prone to chemoresistance and sensitive to the activity of endocrine disrupting chemicals (EDCs), ovarian cancer cells are exposed to a complex biophysical microenvironment in the abdominal cavity ^[1–3]. Retracing molecular events that accompany cancer development and spread, cells were exposed to fluid shear stress, or cultivated on modified ECM stiffness. Exploring signaling pathways inwards and outwards, targeted (microscopy-based) and untargeted (omics-based) analyses were harmonized to investigate whether chemical-driven cascades can affect cell capacity to withstand mechanical stimulation and, in turn, how physical preconditioning can possibly tune cellular response to xenobiotics. Considering molecular effectors that play an acknowledged role in carcinogenesis and might sustain pathway interaction with xenobiotics, a special focus was given to mechanosensitive transcription factors (TFs), including Krüppel-like factors (KLFs), the Nuclear factor erythroid 2-related factor 2 (Nrf2), Sterol regulatory element-binding proteins (SREBPs) or the Yes1 associated transcriptional regulator (YAP1) 4, 5, 6, 7. Tailored physical and chemical manipulation of the TFs translocation patterns enabled the definition of cell-line specific functional performances, such as the regulation of cancer cell proliferation and metabolism, ROS management or the response to cytotoxic insults. Taken together, these data contribute to elucidating molecular mechanisms of toxicity that can be tuned by chemical and physical cues. These promise to be of relevance when extending the use and application of organ-on-chip platforms and support the identification of synergistic or antagonistic interactions in the evaluation of xenobiotics with complex cell culture systems.