Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis
Joseph L. Regan,
Dirk Schumacher,
Stephanie Staudte,
Andreas Steffen,
Ralf Lesche,
Joern Toedling,
Thibaud Jourdan,
Johannes Haybaeck,
Nicole Golob-Schwarzl,
Dominik Mumberg,
David Henderson,
Balázs Győrffy,
Christian R.A. Regenbrecht,
Ulrich Keilholz,
Reinhold Schäfer,
Martin Lange
Affiliations
Joseph L. Regan
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany; Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Corresponding author
Dirk Schumacher
Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
Stephanie Staudte
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany; German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany; Department of Radiation Oncology and Radiotherapy, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
Andreas Steffen
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
Ralf Lesche
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany; Nuvisan ICB GmbH, 13353 Berlin, Germany
Joern Toedling
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany; Nuvisan ICB GmbH, 13353 Berlin, Germany
Thibaud Jourdan
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
Johannes Haybaeck
Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
Nicole Golob-Schwarzl
Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Department of Dermatology and Venereology, Medical University of Graz, 8036 Graz, Austria
Dominik Mumberg
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
David Henderson
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany; Bayer AG, Business Development and Licensing and Open Innovation, Pharmaceuticals, 13342 Berlin, Germany
Balázs Győrffy
Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary; TTK Cancer Biomarker Research Group, Institute of Enzymology, 1117 Budapest, Hungary
Christian R.A. Regenbrecht
Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; CELLphenomics GmbH, 13125 Berlin, Germany; Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
Ulrich Keilholz
Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
Reinhold Schäfer
Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
Martin Lange
Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany; Nuvisan ICB GmbH, 13353 Berlin, Germany
Summary: Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPositive CSCs from colon cancer patient-derived organoids (PDOs) and xenografts (PDXs) showed CSCs to be enriched for neural development genes. Functional analyses of genes differentially expressed in CSCs from PDO and PDX models demonstrated the neural crest stem cell (NCSC) regulator EGR2 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator HOX genes and the neural stem cell and master cell fate regulator SOX2. These data support CSCs as the source of tumor neurogenesis and suggest that targeting EGR2 may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.
