Project title: Finding the causes of small intestinal neuroendocrine tumors

Matthew Meyerson, MD, PhD; Eric Nakakura, MD, PhD; Chrissie Thirlwell, MD, PhD Dana-Farber Cancer Institute, University College London Cancer Institute, University of California - San Francisco

• Status: Completed
• Year(s): 2017
• Grant Type: Accelerator
• Research Type: Basic
• Primary Tumor Site: Small intestine
• Area of Inquiry: Mapping NET dependencies

Outcomes:

Small intestinal neuroendocrine tumors frequently present as multifocal lesions, but the molecular mechanisms underlying their development remain unclear. The goal of this Accelerator Award has been to find the root cause(s) of small intestinal neuroendocrine tumors using advanced technologies that allow us to read the DNA and RNA in cells on a massive scale. Our research has focused on the identification of potential DNA changes that have occurred later in life, environmental influences, and infectious agents that could underlie the growth and development of small intestinal neuroendocrine tumors. We have also studied the cellular composition and heterogeneity of these tumors in detail. During the funding period, we have shown that multifocal primary tumors within the same small bowel infrequently share similar DNA changes, suggesting that the tumors arise independently of each other. We have also observed in patients with multiple metastases that the metastases can originate from either one single primary tumor or several different primary tumors, emphasizing the need to identify and remove all primary tumors at the time of surgery. Our research on epigenetic changes in small intestinal neuroendocrine tumors has provided new candidate epigenetic drivers, and additional evidence for the independent nature of multifocal small intestinal neuroendocrine tumors. An epigenetic change affects how our genes work without changing our DNA’s core instructions and can be influenced by our environment. Further investigation into environmental causes of multifocal small intestinal neuroendocrine tumors, has revealed highly patient-specific microbial communities present in the tumors at the time of surgical resection, and suggested that the tumor-resident microorganisms are unlikely involved in their pathogenesis. Our most recent findings related to the tumor microenvironment of multifocal small intestinal neuroendocrine tumor patients indicate that the tumors consist of spatially distinct tumor cell subtypes affected by interactions with their local cellular environment. We have also successfully used the transcriptomic profile of about 300 enterochromaffin cells, the putative cells-of-origin for small intestinal neuroendocrine tumors, as a reference for cancer-to-normal cell comparisons, revealing several statistically significant differentially expressed genes. In conclusion, this project provides evidence for major genomic and epigenomic diversity among the multifocal small intestinal neuroendocrine tumors within the same small bowel, and cellular heterogeneity within the tumors. Our findings highlight the need for the development of optimized targeted treatments for patients with small intestinal neuroendocrine tumors and provide robust empirical foundations for future work in the field.