Loss of DRO1/CCDC80 in the tumor microenvironment promotes carcinogenesis
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Jessica I. Christian1,*, Agnieszka Pastula2,*, Andreas Herbst3,4, Jens Neumann5, Maximilian K. Marschall1, Andrea Ofner3, Heike Zierahn1, Marlon R. Schneider1, Eckhard Wolf1, Michael Quante2 and Frank T. Kolligs3,6,7,8
1 Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
2 Gastroenterologie II, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
3 Department of Medicine II, Ludwig Maximilian University of Munich, 81377 Munich, Germany
4 Institute of Laboratory Medicine, University Hospital, Ludwig Maximilian University of Munich, 81377 Munich, Germany
5 Institute of Pathology, Ludwig Maximilian University of Munich, 80337 Munich, Germany
6 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
7 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
8 Department of Internal Medicine and Gastroenterology, HELIOS Klinikum Berlin-Buch, 13125 Berlin, Germany
* These authors contributed equally to this work
|Jessica I. Christian,||email:||firstname.lastname@example.org|
Keywords: DRO1; CCDC80; colorectal cancer; tumor microenvironment; tumor suppressor
Received: July 09, 2021 Accepted: September 04, 2021 Published: PUBLISHED_DATE
Tumors are composed of the tumor cells and the surrounding microenvironment. Both are closely interwoven and interact by a complex and multifaceted cross-talk which plays an integral part in tumor initiation, growth, and progression. Dro1/Ccdc80 has been shown to be a potent suppressor of colorectal cancer and ubiquitous inactivation of Dro1/Ccdc80 strongly promoted colorectal carcinogenesis in ApcMin/+ mice and in a chemically-induced colorectal cancer model.
The aim of the present study was to investigate whether Dro1/Ccdc80’s tumor suppressive function is tumor-cell-autonomous. Expression of Dro1/Ccdc80 in cancer cells had no effect on both colon tumor development in ApcMin/+ mice and formation of xenograft tumors. In contrast, DRO1/CCDC80 loss in the microenvironment strongly increased tumor growth in xenograft models, inhibited cancer cell apoptosis, and promoted intestinal epithelial cell migration. Moreover, stromal Dro1/Ccdc80 inactivation facilitated formation of intestinal epithelial organoids. Expression analyses showed Dro1/Ccdc80 to be significantly down-regulated in murine gastric cancer associated fibroblasts, in ApcMin/+ colon tumor primary stromal cells and in microdissected stroma from human colorectal cancer compared to normal, non-tumor stroma. Our results demonstrate epithelial derived DRO1/CCDC80 to be dispensable for intestinal tissue homeostasis and identify Dro1/Ccdc80 as tumor suppressor in the tumor microenvironment.
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