Application of a Multiomics Imaging Workflow to Explore Asparlas Treatment in Solid Tumors.

In acute lymphoblastic leukemia (ALL), hypermethylation of the asparagine synthetase (ASNS) gene promoter, leading to low levels of ASNS in tumor cells, is recognized as a prognostic biomarker, and l-asparaginase-based treatments (e.g., Asparlas) are frequently administered to these patients. In these cancers, tumor cells rely on external asparagine, and its depletion in the bloodstream results in tumor cell apoptosis. A multiomics (imaging) workflow is required to evaluate key molecular changes and characterize solid tumors to explore the potential efficacy of Asparlas in solid tumors. This study introduces a multiomics imaging workflow applicable to solid tumor specimens for the comprehensive molecular profiling of Asparlas treatment effects. The workflow integrates matrix-assisted laser desorption-ionization mass spectrometry imaging (MALDI-MSI), liquid chromatography coupled with high-resolution mass spectrometry, and histopathological staining on consecutive tumor tissue sections. It enables the detection and analysis of metabolites, lipids, and proteins. Tumor characterization was achieved through histology and clustering analysis based on lipid signatures, yielding consistent annotations. On-tissue chemical derivatization followed by MALDI-MSI was performed to assess metabolic alterations, with a focus on amino acids. ASNS distribution was mapped utilizing targeted MALDI-immunohistochemistry, followed by untargeted (spatial) proteomics on adjacent tissue sections. This study established a multiomics imaging approach and demonstrated its applicability in elucidating the metabolic changes in tumor tissue consequent to Asparlas treatment. Furthermore, it highlights the added value of multiomics imaging in pharmaceutical research and development.