(P 130) INVESTIGATING LCP1-MEDIATED ONCOGENIC SIGNALING IN CHONDROSARCOMA METASTASIS

Objective: Chondrosarcoma (CSA) is an aggressive malignancy of bone that lacks effective adjuvant therapies. There is an urgent need to identify mediators of metastasis for therapeutic targets. Prior work in our lab pinpointed lymphocyte cytosolic protein 1 (LCP1) as a driver of metastasis. While LCP1 is known for actin-bundling, some literature also suggests a role in oncogenic signaling, specifically JAK/STAT activation. This study aimed to investigate the role of LCP1 in modulating JAK/STAT signaling in CSA cells.

Methods: To identify LCP1’s key binding partners, a bio-proximity labeling assay was performed. A phospho-microarray assessed the dependence of LCP1 on the activation states of a panel of JAK/STAT proteins. Validataion of STAT3 expression/activation in LCP1 wildtype and knockdown CSA cells was performed via ELISA with and without interleukin-6 (IL-6) stimulation. IL6-induced STAT3 nuclear localization in these cells was assessed via immunofluorescence. Statistical analysis was performed using GraphPad Prism software with ANOVA significance threshold set as p≤0.05.

Results: Bio-proximity labeling revealed that LCP1 interacts with key JAK/STAT signaling molecules—including STAT3 and IL6-associated receptor proteins. IL-6 induced STAT3 phosphorylation increased with reduced LCP1 (p=0.02). Immunofluorescence showed disrupted cytoskeletal architecture in the setting of LCP1 loss, with impaired IL-6 induced STAT3 nuclear localization.

Conclusion: This study demonstrated a novel role for LCP1 in oncogenic signal transduction. LCP1 interacts in close proximity to key components of interleukin mediated STAT activation- specifically, the absence of LCP1 disrupts cytoskeletal architecture and subcellular trafficking of STAT3. These findings further implicate LCP1 as a key regulator of oncogenic signaling, and highlight additional potential therapeutic targets for high grade CSA.