Cross-Species Investigations Reveal Role, Mechanism and Predictive Power of Paracrine, Secondary Senescence in B-Cell Lymphoma Therapy

摘要: Abstract 3715 Apoptosis and cellular senescence operate as anti-tumor safeguard mechanisms. Unlike apoptotic cells, senescent cells remain viable, and, hence, may crosstalk to other in their vicinity over extended periods of time. In fact, that entered oncogene-induced or anticancer therapy-induced (TIS) present with a senescence-associated secretory phenotype (SASP), massive production secretable factors, which reportedly reinforces through an intracellular mechanism. Utilizing the Eμ- myc transgenic mouse lymphoma model, we provide evidence for outcome-relevant paracrine, DNA damage-independent secondary program (SecS) vitro vivo . Apoptosis-blocked (bcl2-infected) from different genetic backgrounds were treated DNA-damaging agent adriamycin alkylating cyclophosphamide upon formation mice TIS SecS was detected based on b-galactosidase activity (SA-b-gal), Ki67 staining BrdU incorporation. The secretome analyzed by proteomics, gene expression protein arrays. Overall progression free survival patients assessed Kaplan-Meier analysis. Transcriptome analyses followed functional studies found extracellular matrix proteins, especially small leucine-rich proteoglycans (SLRP), but not NF-kB-dependent cytokines chemokines, induce proliferating paracrine fashion, linked “high secretor” status stronger induction. Dissecting senescence-mediating pathways recipient biochemical, pharmacological means unveiled essential role LDL receptor-related 1 (LRP1), receptor SLRP SASP components, cell-cycle inhibitor p21 CIP1 SecS. Accordingly, harboring TIS-capable genetically SecS-defective lymphomas ( e.g. lacking LRP1 expression) experienced inferior long-term outcome therapy. Not only cell-based also biologically distinct donor secretor signature stratified mice. Strikingly, humanized versions both classifiers predictive large cohort diffuse B-cell (DLBCL) patients, where they identified – although composed sets largely overlapping patient subgroups superior prognosis, again suggesting critical underlying treatment effector principle. Our study highlights power DLBCL, provides examples (which will be discussed at meeting) SASP-related non-genotoxic pro-senescent therapies. Disclosures: No relevant conflicts interest declare.