2020/11/18
Keio University School of Medicine
RIKEN
A research group led by Professor Toshiro Sato and Project Assistant Professor Kenta Kawasaki of The Sakaguchi Laboratory (Organoid Medicine) at the Keio University School of Medicine, and Team Leader Hidetou Nakagawa of the Laboratory for Cancer Genomics at the RIKEN Center for Integrative Medical Sciences, has successfully created a large-scale library (biobank) of 25 lines. This was achieved in a joint study with the Departments of Gastroenterology and Hepatology, Respiratory Medicine, and General and Gastroenterological Surgery at the Keio University School of Medicine; the Division of Pharmacotherapeutics, Faculty of Pharmacy; The University of Tokyo; Tokyo Medical and Dental University; and the National Cancer Center Hospital. The group collected human hepatobiliary-pancreatic and gastrointestinal neuroendocrine cancer cells—for which research has been limited due to the rarity of the disease—over five years and cultured large quantities of the tumor cells using a technology called organoids.
This has enabled comprehensive molecular analysis, and through repeated analyses, including whole-genome sequencing,
(1) In neuroendocrine cancers, the expression of transcription factors known to be expressed in digestive tissues is reduced compared to normal tissues, while transcription factors such as NKX2-5, which are normally found in the heart muscle, are frequently highly expressed.
(2) Neuroendocrine cancers can grow even in an environment lacking growth factors such as Wnt and EGF, which are necessary for the growth of normal cells.
(3) Chromosomes are dynamically rearranged throughout neuroendocrine cancers, and abnormalities in the gene expression program are caused by changes in information other than the DNA base sequence (epigenome).
the study revealed these and other characteristics for the first time.
Furthermore, using a gene-editing technology called CRISPR-Cas9, the research team successfully reconstructed neuroendocrine cancer from cultured normal cells by artificially introducing mutations found in neuroendocrine cancers into the genes of normal colon cells. This result showed for the first time that the loss of the two tumor suppressor genes TP53 and RB1, traditionally considered a hallmark of neuroendocrine cancer, is not sufficient on its own to confer the properties of neuroendocrine cancer, and that the activation of multiple other factors, such as NKX2-5, is also required.
The results of this research provide a foundational research resource for neuroendocrine cancer, for which research materials have been scarce. This will contribute to the promotion of rare cancer research and is expected to lead to a further understanding of the pathology of this disease and the development of new drugs.
Details of this research were published online in the scientific journal "Cell" on November 6, 2020 (US Eastern Time). It will also be published in the scientific journal "Cell" on November 25, 2020 (US Eastern Time).
Please see below for the full press release.