Abstract 371: Integrin-mediated lipolysis by pancreatic cancer-derived extracellular vesicles in cancer-associated cachexia

Abstract

Abstract Introduction: Cancer-associated cachexia (CAC) is a life-threating condition frequently observed in cancer patients, especially those with pancreatic cancer. CAC is a multifactorial disease, with the notable characteristic of systemic lipolysis. Although humoral factors have been implicated in its pathogenesis, critical factors remain to be determined. Since even localized pancreatic cancer frequently induce lipolysis systemically, we examined the molecular mechanisms in vitro and in vivo based on the hypothesis that extracellular vesicles (EVs) systemically released from pancreatic cancer cells induce lipolysis. Procedures: EVs derived from the supernatants of cultured pancreatic cancer cell lines and from the sera of pancreatic cancer patients were characterized. The effects of EVs on adipocytes were determined using mature human adipocytes induced from human adipose-derived mesenchymal stem cells. To confirm the in vitro findings, lipolysis induction was examined in mice by intravenous injection of EVs. EV characteristics inducing lipolysis were determined. Those characteristics were confirmed by knockout studies and examining specifically isolated pancreatic cancer-derived EVs from heterogenous EV population in patients’ sera. Results: Lipolysis was triggered by specific EVs from pancreatic cancer cell line via the cAMP inside and uptake of more EVs into adipocytes was crucial for higher levels of lipolysis. In vivo studies, database search, and knockout studies revealed that integrin β1 and integrin α6 on EVs were the determinants for the attachment and uptake of the EVs to adipocytes, resulting in inducing more lipolysis. There was no difference in the percentage of these integrins positive EVs between heterogenous EV population in cancer patients’ sera and EVs in cancer-free controls’ sera. However, pancreatic cancer cell-derived EVs specifically isolated by targeting CA19-9, an aberrant glycosylation, from heterogenous EV population in patients’ sera, confirmed that pancreatic cancer-derived EVs have more such integrins. Conclusions: Cancer cell-derived EVs in the sera of pancreatic cancer patients have more ITGB1 and ITGA6 levels, which may explain the systemic induction of lipolysis in cancer cachexia from the early stages and could be novel therapeutic targets against CAC. In addition, specific isolation of cancer-derived EVs in sera from heterogenous EV population is crucial for elucidating cancer-related pathogenesis. Citation Format: Chikako Shibata, Motoyuki Otsuka, Mitsuhiro Fujishiro. Integrin-mediated lipolysis by pancreatic cancer-derived extracellular vesicles in cancer-associated cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 371.