3.8 Article

Loss of Dok-3 in Non-tumor Cells Induces Malignant Transformation of Benign Epithelial Tumor Cells of the Intestine

Journal

CANCER RESEARCH COMMUNICATIONS
Volume 2, Issue 12, Pages 1590-1600

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2767-9764.CRC-22-0347

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Funding

  1. JSPS KAKENHI [15H05574, 18K19470]
  2. Research Foundation for Microbial Diseases of Osaka University

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The fundamental difference between benign and malignant tumors lies in their invasive ability. The study found that the loss of the Dok-3 tumor suppressor gene led to malignant progression in a benign tumor model. However, this transformation was caused by a mechanism outside of the tumor cells.
The fundamental difference between benign and malignant tumors lies in their invasive ability. It is believed that malignant conversion of benign tumor cells is induced by a tumor cell-intrinsic accumulation of driver gene mutations. Here, we found that disruption of the Dok-3 tumor sup-pressor gene led to malignant progression in the intestinal benign tumor model ApcMin/+ mice. However, Dok-3 gene expression was undetectable in epithelial tumor cells and the transplantation of bone marrow cells lacking the Dok-3 gene-induced malignant conversion of epithelial tumor cells in ApcMin/+ mice, indicating a previously unrecognized tumor cell- extrinsic mechanism. Moreover, the Dok-3 loss-induced tumor invasion in ApcMin/+ mice required CD4+ and CD8+ T lymphocytes, but notB lymphocytes. Finally, whole-genome sequencing showed an indistin-guishable pattern and level of somatic mutations in tumors irrespective of the Dok-3 gene mutation in ApcMin/+ mice. Together, these data indicate that Dok-3 deficiency is a tumor-extrinsic driving force of ma-lignant progression in ApcMin/+ mice, providing a novel insight into microenvironments in tumor invasion.

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