New research has identified dedicator of cytokinesis 10 (DOCK10) as a potential diagnostic marker and therapeutic target in insulinoma, offering new insight into the mechanisms underlying inappropriate insulin secretion.
Insulinomas are rare pancreatic neuroendocrine tumors that can cause clinically significant hypoglycemia. Although imaging and functional tests are used to localize these tumors, identifying which lesions are actively secreting insulin can be difficult, particularly in patients with multiple tumors or metastatic disease.
In a study published in Cellular and Molecular Gastroenterology and Hepatology, researchers analyzed human insulinoma samples alongside patient-derived organoids using transcriptomic techniques, including RNA sequencing and immunohistochemistry. Across these datasets, DOCK10 was consistently overexpressed in insulin-secreting tumor components compared with normal pancreatic tissue and nonfunctional neuroendocrine tumors.
Importantly, DOCK10 expression showed strong specificity at the protein level. Immunostaining demonstrated that DOCK10 was present in insulinoma tissue but largely absent in non-secreting tumors. In cases where patients had both secreting and non-secreting lesions, DOCK10 staining more accurately identified the clinically active lesions than insulin staining alone.
This distinction is relevant for diagnostic practice. Insulin immunostaining can be positive in some nonfunctional tumors, which may not correspond to clinical hormone secretion. The study found that DOCK10 expression aligned more closely with functional activity, suggesting it could serve as a more reliable marker for identifying insulin-secreting tumor cells.
Single-cell RNA sequencing further supported these findings by showing that DOCK10 expression is enriched in specific tumor cell populations associated with active insulin secretion. This highlights the heterogeneity within insulinomas and suggests that DOCK10 may help distinguish functional subpopulations within a tumor.
Functional experiments provided additional context. Reducing DOCK10 expression in insulinoma cell models decreased glucose-stimulated insulin secretion without affecting insulin production, indicating that DOCK10 plays a role in the secretion process. The study also identified a downstream signaling pathway involving Cdc42, and pharmacologic inhibition of this pathway reduced insulin hypersecretion in both cell and animal models.
These findings suggest that DOCK10 could complement existing markers when evaluating pancreatic neuroendocrine tumors. Its ability to distinguish insulin-secreting from non-secreting lesions may be particularly useful in complex cases, such as metastatic disease or multifocal tumors.
The study also established organoid models that maintained insulin secretion over time, providing a platform for future diagnostic and therapeutic research.
Limitations include a relatively small sample size and limited single-cell data, as well as the use of adjacent pancreatic tissue rather than fully normal controls.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
