By Anna Greene, PhD, Chief Scientific Officer, Neuroendocrine Tumor Research Foundation
At NETRF, we often talk about the importance of funding foundational science. These studies may not immediately change clinical care, but they provide the field with the biological understanding needed to develop better diagnostics, treatments, and more precise strategies for patients in the future.
A newly published study in The Journal of Clinical Investigation is a strong example of why this kind of research makes a difference. The study, first-authored by Pratik N.P. Singh, PhD, and led by researchers including Ramesh Shivdasani, MD, PhD, examined small-intestinal neuroendocrine tumors, or SI-NETs, in relation to the normal cells in the intestine that they most closely resemble. NETRF supported this work through a Peterson Accelerator Award to the late Dr. Qiao Zhou, PhD, and Dr. Shivdasani.
Small-intestinal NETs are the most common primary cancer arising in the small intestine. They are often slow-growing, but they are difficult to study and difficult to treat once they have spread. One reason progress has been challenging is that these tumors do not look genetically like many other cancers. They often do not carry the same kinds of common cancer-driving mutations seen in other tumor types. Instead, they appear to be shaped by subtle changes in how cells grow, mature, and regulate gene activity.
To understand this, it helps to start with the normal intestine. The intestine contains specialized hormone-producing cells called enteroendocrine cells. These cells help regulate digestion, metabolism, and communication between the gut and the rest of the body. They comprise less than 1% of the intestinal lining, making it difficult to compare normal enteroendocrine cells with small-intestinal NET cells in detail.
The study by Singh and colleagues used advanced tools to look at several layers of tumor biology at once, including which genes were turned on, which regions of DNA were active, and how tumor cells compared with normal enteroendocrine cells as they develop from intestinal stem cells into mature hormone-producing cells. In simpler terms, the researchers asked where do these tumor cells fit along the normal path of intestinal cell development?
The answer was both surprising and informative.
The researchers found that most small-intestinal NET cells strongly resemble mature enterochromaffin cells, a type of enteroendocrine cell that produces the hormone serotonin. But the tumor cells also retained features of much earlier, less mature intestinal stem and progenitor cells. In normal development, cells usually move through these stages in sequence. In these tumors, individual tumor cells appeared to carry features from multiple stages at the same time.
As Dr. Shivdasani explains, “This phenomenon is unusual in human cancers. The cells in most cancers are arrested at an immature stage in normal cell development, so they keep making copies of themselves and never reach the terminal stage of a cell’s physiologic functions. By contrast, the cells in small intestinal NETs are almost terminally mature but remain able to replicate indefinitely, albeit slowly. Our study traced this unusual dual character to specific changes in the way DNA is packaged in the cell nucleus. In small intestinal NETs, that packaging precludes the normal progression of dividing enteroendocrine cells into eventual maturity and death. Instead, the DNA in the cancer cells is abnormally programmed to skip an essential quality-control step in the normal life cycle. They therefore persist in a prolonged suspended state that allows cells to divide even as they mature into hormone (serotonin)-producing cancer cells. These findings will lead to devising strategies that can restore the normal balance, allowing cancer cells to live only a few days, like normal enteroendocrine cells, and not indefinitely.”
That finding is significant because it suggests that small-intestinal NETs are not simply “stuck” at one immature stage. Instead, they may represent an unusual cell state that combines mature hormone-producing features with earlier growth and developmental programs. This could help explain why these tumors behave differently from more aggressive neuroendocrine carcinomas and from many other cancers.
One of the most important findings involved two genes called ASCL1 and NEUROD1, which help guide neuroendocrine cell development. The study found that the dominant group of small-intestinal NETs consistently expressed NEUROD1 but lacked ASCL1. In normal enteroendocrine cell development, ASCL1 appears during an intermediate stage and helps control the timing and fidelity of cell maturation. In the tumor cells, ASCL1 is tightly silenced by the way its specific DNA is packaged.
A simple way to think about this is as a missing checkpoint in the normal developmental program. If normal intestinal endocrine cells follow a carefully timed set of instructions as they mature, these tumor cells seem to have bypassed or silenced part of that instruction set. The result may be a cell that looks mature in some ways but still retains abnormal developmental flexibility.
The study also examined genes that help control the cell cycle, the process by which cells decide whether to divide. One gene, CDKN1B, is especially important because it is the only gene known to be recurrently mutated in small-intestinal NETs. The researchers found that several other cell-cycle “brake” genes were silenced in these tumors, potentially making the cells unusually dependent on CDKN1B and related pathways to keep growth under control.
This study does not change treatment today, but it gives researchers a clearer map of small-intestinal NET biology. That map can help the field build better models and pursue more precise treatment strategies over time.
For NETRF, this is exactly the kind of research we aim to catalyze. Neuroendocrine cancer research has historically been underfunded, and many basic questions about NET biology remain unanswered. By supporting investigators who are building the foundational knowledge of how these tumors arise and persist, we help create the conditions for future translational progress in the clinic.
The path from discovery to patient impact is rarely immediate. But every meaningful advance in cancer care begins with a clearer understanding of the disease. NETRF is proud to have supported research that brings us closer to that understanding for small-intestinal neuroendocrine tumors.
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Read the full study in The Journal of Clinical Investigation: Multiomic analyses delineate human neuroendocrine tumor cell states in relation to normal enteroendocrine cell ontogeny, and learn more about NETRF-funded research.