Diverse transcriptomic and mutational patterns but limited functional pathway alterations in patient-derived SS cells

Abstract

Structured AbstractO_ST_ABSBackgroundC_ST_ABSEradication of SS is hampered by its genetic and molecular heterogeneity. A better understanding of the putative commonalities underlying SS oncogenicity may help to provide more efficient therapeutic strategies against this devastating disease. PurposeThe present work analyzes the whole transcriptome of different patient-derived SS cells to identify expression patterns, functional programs and expressed gene mutations that may provide clues on new therapeutic options for SS patients MethodsMononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of SS patients (n=7). Selected pathway-based compounds and the MALT1 inhibitor MI2 were used for in vitro drug sensitivity testing. SS cells viability was evaluated using CellTiter-Glo_3D Cell Viability Assay and flow cytometry analysis. We validated the usefulness of MI2 using patient-derived SS cells xenotransplanted (PDX) into Nod Scid Gamma mice. ResultsIn vitro data indicated that cell lines and primary malignant SS cells all display different sensitivities against specific pathway inhibitors. However, MALT1 inhibition led to a robust effect in vitro that was partially reproduced in the in vivo NSG mice xenograft model. ConclusionOur investigations revealed the actual possibility of inhibiting the downstream TCR signaling complex form by CARD11, BCL10 and MALT1 in SS therapy. Key PointsPatient-derived SS cells are transcriptionally and mutationally heterogeneous but share some common pathway alterations. Inhibition of MALT1 reduces NF-{kappa}B signaling and cell growth in cell lines and patient-derived SS cells.