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

doi:10.1016/j.isci.2022.104498

Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis

iScience. 2022 May 31;25(7):104498. doi: 10.1016/j.isci.2022.104498. eCollection 2022 Jul 15.

Authors

Joseph L Regan^{1

2}, Dirk Schumacher^{3

4}, Stephanie Staudte^{1

4

5}, Andreas Steffen¹, Ralf Lesche^{1

6}, Joern Toedling^{1

6}, Thibaud Jourdan¹, Johannes Haybaeck^{7

8}, Nicole Golob-Schwarzl^{7

9}, Dominik Mumberg¹, David Henderson^{1

10}, Balázs Győrffy^{11

12}, Christian R A Regenbrecht^{3

13

14}, Ulrich Keilholz², Reinhold Schäfer^{2

3

4}, Martin Lange^{1

6}

Affiliations

¹ Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany.
² Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
³ Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁴ German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany.
⁵ Department of Radiation Oncology and Radiotherapy, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁶ Nuvisan ICB GmbH, 13353 Berlin, Germany.
⁷ Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁸ Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria.
⁹ Department of Dermatology and Venereology, Medical University of Graz, 8036 Graz, Austria.
¹⁰ Bayer AG, Business Development and Licensing and Open Innovation, Pharmaceuticals, 13342 Berlin, Germany.
¹¹ Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary.
¹² TTK Cancer Biomarker Research Group, Institute of Enzymology, 1117 Budapest, Hungary.
¹³ CELLphenomics GmbH, 13125 Berlin, Germany.
¹⁴ Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Abstract

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 ALDH^Positive 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.

Keywords: Cancer; Stem cells research; Transcriptomics.