Deadly reversion

A study led by Ludwig Lausanne’s Douglas Hanahan and published in an April issue of Cancer Discovery described a previously unrecognized mechanism by which cancer cells of a relatively benign subtype of pancreatic tumors methodically revert—or “de-differentiate”—to a progenitor, or immature, state of cellular development to spawn aggressive, metastatic tumors. Engagement of the mechanism is associated with poorer outcomes in patients diagnosed with pancreatic neuroendocrine tumors (PanNETs). These tumors originate from the islet beta-cells of the pancreas and can be divided into a relatively benign, well-differentiated subtype that maintains many features of insulin-producing beta cells, and an aggressive, poorly differentiated subtype that lacks those features. Using a PanNET mouse model, Doug and his colleagues showed that the progression from benign to aggressive PanNET tumors requires cancer cells to retrace the pathway of beta cell differentiation and maturation to assume the progenitor state. Tumor cells poised to de-differentiate step up production of microRNA18, which ultimately causes the activation of Hmgb3, a protein that controls the expression of a suite of genes that induce the progenitor state. The study furnishes preliminary evidence supporting the inclusion of dedifferentiation as a distinct and separable step, or perhaps sub-step, in the journey to malignancy.

This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).


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