RESUMEN
Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.
Asunto(s)
Linfoma de Células B Grandes Difuso , Microambiente Tumoral , Humanos , Línea Celular Tumoral , Transducción de Señal , FN-kappa B/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismoRESUMEN
Biological sex differences are observed at multiple different length scales and across organ systems. Gaps in knowledge remain regarding our understanding of how molecular, cellular, and environmental factors contribute to physiological sex differences. Here, we provide our perspective on how chemical and molecular tools can be leveraged to explore sex differences in biology at the molecular, intracellular, extracellular, tissue, and organ length scales. We provide examples where chemical and molecular tools were used to explore sex differences in the cardiovascular, nervous, immune, and reproductive systems. We also provide a future outlook where chemical and molecular tools can be applied to continue investigating sex differences in biology, with the ultimate goal of addressing inequities in biomedical research and approaches to clinical treatments.