OC45 - IL-1β/CXCL12 axis drives the crosstalk between PanNET cells and adipocytes

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Abstract Background/Introduction Pancreatic neuroendocrine tumors (PanNETs) are rare malignancies arising from pancreatic endocrine cells, representing less than 3% of all primary pancreatic cancers. While generally less aggressive than pancreatic ductal adenocarcinoma, PanNETs often display metastatic behavior. Emerging evidence suggests that obesity and visceral fat accumulation may promote PanNET progression. However, the specific role of adipocytes in this context remains poorly understood. Purpose This study investigates whether PanNET cells can reprogram adipocytes into cancer-associated adipocytes (CAAs), thereby contributing to tumor growth. Methods Human PanNET cell lines BON-1 and QGP-1 were used as tumor models. Differentiated 3T3-L1 adipocytes mimicked adipose tissue. Tumor–adipocyte interactions were assessed using MTT assays, Oil Red O staining, RT-PCR, and ELISA. Adipocyte phenotypic changes and tumor cell proliferation were assessed following exposure of adipocytes to PanNET-conditioned media and of PanNET cells to adipocyte-conditioned media, respectively, or through indirect co-culture. Results Conditioned media from PanNET cells induced only mild morphological and transcriptional changes in adipocytes. In contrast, indirect co-culture triggered pronounced adipocyte reprogramming, characterized by lipid depletion, enhanced lipolytic activity, and downregulation of adipogenic markers such as PPARγ, leptin, and FABP4—hallmarks of CAAs. In this context, the conversion of adipocytes into CAAs appeared to be driven by the secretion of the pro-inflammatory cytokine IL-1β by PanNET cells. Notably, inhibition of IL-1β secretion significantly reduced this phenotypic transition. Concurrently, IL-1β production was closely associated with increased CXCL12 expression in CAAs. CXCL12, a chemokine known to support tumor cell proliferation, appeared to play a central role in promoting PanNET cell growth. This reinforces the existence of a reciprocal, pro-tumorigenic feedback loop between tumor cells and reprogrammed adipocytes. Pharmacological inhibition of CXCR4—the receptor for CXCL12—using AMD3100 effectively disrupted this loop, resulting in decreased IL-1β levels, prevention of adipocyte reprogramming, and reduced tumor cell proliferation. Conclusion(s) These findings identify IL-1β and CXCL12 as key mediators of an inflammatory crosstalk between adipocytes and PanNET cells, promoting mutual activation in a feed-forward manner. Targeting this axis pharmacologically may offer a promising therapeutic strategy for PanNETs, particularly in patients with adipose- rich tumor environments.

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