Cancer of the small intestine (SI) is rare and typically presents as Gastrointestinal Neuroendocrine Tumors (SI-NETs). Seminal studies demonstrate that colorectal tumors arise when a complement of transformative mutations occur in colonic stem cells. In contrast, little is known about the cellular origin and underlying biology of SI-NETs. SI-NETs feature an overabundance of hormone-secreting neuroendocrine cells, and are typically undetectable until metastatic tumors cause carcinoid syndrome. Owing to their slow proliferation rate, unknown genetic etiology, and lack of cell culture models that accurately represent disease phenotypes, SI-NETs are technically challenging to study in vivo and represent an understudied cancer that is on the rise. Knowledge gaps in the understanding of oncogenic transformation driving SI-NET initiation, as well as the basic cellular composition of human SI-NETs, have precluded development of much-needed therapeutics. Single ISCs give rise to self- renewing/patterning organoids in culture and currently represent the best, non-transformed, physiologic model of the intestinal epithelium. ISCs in the SI exist as multiple populations defined by different proliferative states. Active ISCs (aISC) are highly undifferentiated and continuously divide to renew the intestinal epithelium. In contrast, reserve ISCs are secretory progenitors, express both neuroendocrine hormones and stem cell biomarkers, and divide very slowly. Recently, CRISPR/Cas9 was used to recapitulate sequential in vivo mutations driving CRC in primary human colonic organoids, providing a powerful model for ?omics level analysis and drug screening of human cancer. We hypothesize that secretory progenitor rISCs accumulate driver mutations, which promote transformation to SI-NETs that are supported by the underlying stromal cells. We will test this hypothesis by, (Aim1) adapting ISC organoids and high-throughput culture arrays to determine the genetic and cellular basis of SI-NET initiation, and (Aim 2) mapping the SI-NET cytome using single-cell RNA-seq.

Public Health Relevance

Small Intestinal Neuroendocrine Tumors (SI-NETs) are rare slow-growing tumors that are understudied but represent a growing class of cancers in the United States. Driver-mutations for SI-NETs and understanding of the tumor microenvironment are unknown and represent a significant gap in knowledge that precludes development of therapies. The goal of this proposal is to develop new methods and use innovative microengineered technologies to test candidate driver mutations and map the cells and heterogeneity of SI-NETs to better understand this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA215900-02
Application #
9471368
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Zahir, Nastaran Z
Project Start
2017-05-01
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599