(P 54) PRECLINICAL MODELS REVEALING MDM2-P53 INTERACTION AND DEPENDENCY FOR TUMOR CELL SURVIVAL IN WELL-DIFFERENTIATED (WD) AND DEDIFFERENTIATED (DD) LIPOSARCOMA (LPS).

Objective: WD and DD LPS are characterized by the amplification (amp) of 12q13-15 chromosomal region, leading to the usage of MDM2 amp as a diagnostic marker. Though WD has low metastatic potential, 10-20% progress to the more aggressive DD. The mechanism underlying transition remains unclear.

Methods: We generated patient (pt) derived xenograft (PDX: 4 WD, 5 DD) and cell culture (PDC:10 WD, 6 DD) models from 105 surgical specimens. The models were characterized with H&E stain, WES, RNA sequencing (RS), FISH, and drug sensitivity assays. The validation was done compared to original pt tumors. The association between MDM2 amp levels and pt prognosis were analyzed. A comparative analysis between WD and DD tumors was done using Reverse-Phase Protein Array (RPPA).

Results: Clinical data showed WD with increased cellularity area had a shorter time to progression into DD and displayed intermediate survival prognosis between pure WD and DD, implying a transitional phenotype. DD tumors had higher MDM2 copy number (CN) compared to WD both within the same and across different pts, while serially resected tumors from the same pts showed no increase in MDM2 CN over time. Moreover, MDM2 CN decreased over serial passages in both PDXs and PDCs suggesting increased MDM2 amp is likely a consequence rather than a driver of DD. RPPA revealed upregulation of DNA repair and hypoxia-related pathways in DD compared to WD. An inverse correlation between MDM2 CN and PPARG RNA expression was found, supporting the association of MDM2 amp with higher grades. It is notable that MDM2 CN did not correlate with MDM2 RNA and protein expression, implying MDM2 amp in high-grade tumors may not directly impact MDM2 functional output. WES and RS of PDXs revealed reduced expression of anaphase-promoting complex: CCNA2 and UBE2C in tumors with higher MDM2 amp, implicating cell cycle dysregulation. Interestingly, analysis of aggressive DD tumors showed increased activation of the p53 pathway despite persistent MDM2 amp, suggesting stronger influence of genomic instability on p53 activation than its suppression by MDM2. Drug testing using models is ongoing.

Conclusion: We successfully developed both WD and DD PDX and PDC models. Chronological changes and functional response unveil complex interaction between MDM2-p53 axis central to understanding the transition between WD and DD and future therapeutic strategies.