Elevated sortilin expression discriminates functional from non-functional neuroendocrine tumors and enables therapeutic targeting

Front Endocrinol (Lausanne). 2024 Apr 17:15:1331231. doi: 10.3389/fendo.2024.1331231. eCollection 2024.

Abstract

A subset of neuroendocrine tumors (NETs) can cause an excessive secretion of hormones, neuropeptides, and biogenic amines into the bloodstream. These so-called functional NETs evoke a hormone-related disease and lead to several different syndromes, depending on the factors released. One of the most common functional syndromes, carcinoid syndrome, is characterized mainly by over-secretion of serotonin. However, what distinguishes functional from non-functional tumors on a molecular level remains unknown. Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome.

Keywords: carcinoid syndrome; enteroendocrine cells; functional syndrome; neuroendocrine tumors; organoids; serotonin; sortilin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport* / metabolism
  • Animals
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Malignant Carcinoid Syndrome / metabolism
  • Mice
  • Middle Aged
  • Neuroendocrine Tumors* / metabolism
  • Neuroendocrine Tumors* / pathology
  • Serotonin* / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • Biomarkers, Tumor
  • Serotonin
  • sortilin

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. MS received funding from the DFG (DFG Si 1984 4/1), Horizon Europe ERC (Starting Grant REVERT (ERC Grant number 101040453)), The Einstein Foundation (EC3R Einstein Center) and the BMBF (PACE Therapy). The authors thank Dr. Monika Gunzenhauser and Gunther Speidel (†) for generous donations.