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Background <p>Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms belonging to the broader group of neuroendocrine neoplasms. Epidemiological evidence indicates that visceral obesity is associated with both an increased incidence of PanNETs and unfavorable clinicopathological features. However, the mechanisms underlying adipocyte–PanNETs interactions remain poorly understood.</p> Methods <p>Here, we investigated the crosstalk between adipocytes and PanNET cells (BON-1 and QGP-1 cell lines) using indirect co-culture systems and conditioned media derived from differentiated 3T3–L1 adipocytes or PanNET cells.</p> Results <p>Our results demonstrate that PanNET cells induce adipocyte reprogramming toward a cancer-associated adipocyte (CAA) phenotype, characterized by lipid depletion and downregulation of adipogenic markers, including <i>Pparg, Fabp4, Hsl</i>, and <i>Atgl</i>. We identified PanNET-derived interleukin-1β (IL-1β) as a key driver of adipocyte conversion into CAAs. This process was accompanied by increased secretion of the chemokine CXCL12 from CAAs, which in turn appeared to enhance PanNET cell proliferation and IL-1β release, thereby establishing a positive bidirectional crosstalk consistent with a feedback-like mechanism between CXCL12 and IL-1β in CAAs and PanNET cells, respectively. Indeed, pharmacological disruption of this axis using AMD3100, a CXCR4 antagonist, significantly reduced both IL-1β and CXCL12 secretion, prevented adipocyte reprogramming, and suppressed tumor cell proliferation. Comparable effects were observed following incubation of PanNET–adipocyte co-cultures with canakinumab, an IL-1β pathway inhibitor.</p> Conclusion <p>Collectively, these findings identify IL-1β and CXCL12 as potential critical mediators of the inflammatory crosstalk between adipocytes and PanNET cells. Targeting this signalling axis may therefore represent a promising therapeutic strategy for PanNETs.</p> Graphical Abstract <p></p>

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IL-1β/CXCL12 signalling orchestrates adipocyte–pancreatic neuroendocrine tumor crosstalk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Monica Oldani,
  • Elisa Stellaria Grassi,
  • Germano Gaudenzi,
  • Ilona Rybinska,
  • Silvia Carra,
  • Elena Massardi,
  • Nicola Fazio,
  • Michele Caraglia,
  • Luca Persani,
  • Giovanni Vitale

摘要

Background

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms belonging to the broader group of neuroendocrine neoplasms. Epidemiological evidence indicates that visceral obesity is associated with both an increased incidence of PanNETs and unfavorable clinicopathological features. However, the mechanisms underlying adipocyte–PanNETs interactions remain poorly understood.

Methods

Here, we investigated the crosstalk between adipocytes and PanNET cells (BON-1 and QGP-1 cell lines) using indirect co-culture systems and conditioned media derived from differentiated 3T3–L1 adipocytes or PanNET cells.

Results

Our results demonstrate that PanNET cells induce adipocyte reprogramming toward a cancer-associated adipocyte (CAA) phenotype, characterized by lipid depletion and downregulation of adipogenic markers, including Pparg, Fabp4, Hsl, and Atgl. We identified PanNET-derived interleukin-1β (IL-1β) as a key driver of adipocyte conversion into CAAs. This process was accompanied by increased secretion of the chemokine CXCL12 from CAAs, which in turn appeared to enhance PanNET cell proliferation and IL-1β release, thereby establishing a positive bidirectional crosstalk consistent with a feedback-like mechanism between CXCL12 and IL-1β in CAAs and PanNET cells, respectively. Indeed, pharmacological disruption of this axis using AMD3100, a CXCR4 antagonist, significantly reduced both IL-1β and CXCL12 secretion, prevented adipocyte reprogramming, and suppressed tumor cell proliferation. Comparable effects were observed following incubation of PanNET–adipocyte co-cultures with canakinumab, an IL-1β pathway inhibitor.

Conclusion

Collectively, these findings identify IL-1β and CXCL12 as potential critical mediators of the inflammatory crosstalk between adipocytes and PanNET cells. Targeting this signalling axis may therefore represent a promising therapeutic strategy for PanNETs.

Graphical Abstract