ORBITA: Organelle-Based Integration of Translocation and Adaptation in Cancer

Abstract

Cancer is currently understood as a disease of dynamic adaptation, in which tumor cells continuously reprogram their metabolism and signaling networks to survive adverse conditions such as oxidative stress and exposure to chemotherapeutic agents. Although these processes have been widely investigated from the perspective of genetic and enzymatic alterations, recent evidence indicates that intracellular spatial organization constitutes a critical regulatory layer that remains insufficiently explored. In this context, the localization and subcellular trafficking of proteins emerge as functional determinants of their activity, enabling the integration of signals across distinct cellular compartments. Among the regulators involved in this process, Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) has emerged as a relevant modulator of tumorigenesis, associated with metabolic reprogramming, redox control, and therapeutic resistance in gastrointestinal cancers, especially colorectal cancer. Thus, this project proposes the establishment of the ORBITA platform (Organelle-Based Integration of Translocation and Adaptation in Cancer), with the objective of investigating how the localization and subcellular trafficking of LMWPTP between organelles may constitute a critical mechanism of adaptation to chemical stress in the context of carcinogenesis (the transformation of normal cells into cancer cells) and tumorigenesis (the formation of benign and malignant tumors), acting as a spatiotemporal integrator of cellular signaling capable of modulating metabolic and survival networks. To validate this hypothesis, the project is structured into five axes: (i) characterization of LMWPTP involvement in shaping the three-dimensional architecture of organelles, as well as their dynamics and functionality under stress; (ii) redistribution of LMWPTP and analysis of its association with functional microdomains; (iii) integrated mapping of signaling pathways and epigenetic control regulating LMWPTP localization; (iv) investigation of bioactive compounds as modulators of spatiotemporal organization; and (v) development of open-source computational tools for quantitative analysis and modeling of spatiotemporal dynamics. For the establishment of the ORBITA platform and validation of these hypotheses, colorectal cancer models in 2D and 3D cultures (spheroids and bioprinted tissue) will be used, combining epigenetic approaches, advanced microscopy, and quantitative image analysis to investigate the three-dimensional organization of organelles, LMWPTP translocation dynamics, and its interaction with protein complexes. The project also includes the development of computational tools for the integrated analysis of these spatiotemporal dynamics. By integrating epigenetic regulation, protein dynamics, and subcellular organization, this study aims to contribute to the definition of an emerging functional principle in cancer biology, in which intracellular architecture acts as an active determinant of tumor adaptation.