Identification of a Neural Development Gene Expression Signature in Colon Cancer Stem Cells Reveals a Role for in Tumorigenesis

Overview

Journal iScience

Publisher Cell Press

Date 2022 Jun 20

PMID 35720265

Authors

Joseph L Regan

Dirk Schumacher

Stephanie Staudte

Andreas Steffen

Ralf Lesche

Joern Toedling

Thibaud Jourdan

Johannes Haybaeck

Nicole Golob-Schwarzl

Dominik Mumberg

David Henderson

Balazs Gyorffy

Christian R A Regenbrecht

Ulrich Keilholz

Reinhold Schafer

Martin Lange

Affiliations

Soon will be listed here.

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 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 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator genes and the neural stem cell and master cell fate regulator . These data support CSCs as the source of tumor neurogenesis and suggest that targeting may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.

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References

Schonkeren S, Thijssen M, Vaes N, Boesmans W, Melotte V . The Emerging Role of Nerves and Glia in Colorectal Cancer. Cancers (Basel). 2021; 13(1). PMC: 7796331. DOI: 10.3390/cancers13010152. View

Bhatlekar S, Fields J, Boman B . Role of HOX Genes in Stem Cell Differentiation and Cancer. Stem Cells Int. 2018; 2018:3569493. PMC: 6081605. DOI: 10.1155/2018/3569493. View

Tsou A, Chuang Y, Su J, Yang C, Liao Y, Liu W . Overexpression of a novel imprinted gene, PEG10, in human hepatocellular carcinoma and in regenerating mouse livers. J Biomed Sci. 2003; 10(6 Pt 1):625-35. DOI: 10.1159/000073528. View

Chavrier P, Vesque C, Galliot B, Vigneron M, Dolle P, Duboule D . The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1.4 gene. EMBO J. 1990; 9(4):1209-18. PMC: 551797. DOI: 10.1002/j.1460-2075.1990.tb08228.x. View

Senga S, Grose R . Hallmarks of cancer-the new testament. Open Biol. 2021; 11(1):200358. PMC: 7881179. DOI: 10.1098/rsob.200358. View

Magnon C, Hall S, Lin J, Xue X, Gerber L, Freedland S . Autonomic nerve development contributes to prostate cancer progression. Science. 2013; 341(6142):1236361. DOI: 10.1126/science.1236361. View

Davis E, Dailey M . A direct effect of the autonomic nervous system on somatic stem cell proliferation?. Am J Physiol Regul Integr Comp Physiol. 2018; 316(1):R1-R5. DOI: 10.1152/ajpregu.00266.2018. View

Regan J, Schumacher D, Staudte S, Steffen A, Lesche R, Toedling J . RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence. iScience. 2021; 24(6):102618. PMC: 8185225. DOI: 10.1016/j.isci.2021.102618. View

Novak D, Huser L, Elton J, Umansky V, Altevogt P, Utikal J . SOX2 in development and cancer biology. Semin Cancer Biol. 2019; 67(Pt 1):74-82. DOI: 10.1016/j.semcancer.2019.08.007. View

10.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

11.

Jiang Y, Oblinger M . Differential regulation of beta III and other tubulin genes during peripheral and central neuron development. J Cell Sci. 1992; 103 ( Pt 3):643-51. DOI: 10.1242/jcs.103.3.643. View

12.

Adameyko I, Lallemend F, Aquino J, Pereira J, Topilko P, Muller T . Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell. 2009; 139(2):366-79. DOI: 10.1016/j.cell.2009.07.049. View

13.

Jiang S, Hu L, Wang X, Li J, Zhang Z . Neurotransmitters: emerging targets in cancer. Oncogene. 2019; 39(3):503-515. DOI: 10.1038/s41388-019-1006-0. View

14.

Morrison S, White P, Zock C, Anderson D . Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell. 1999; 96(5):737-49. DOI: 10.1016/s0092-8674(00)80583-8. View

15.

Vesque C, Maconochie M, Nonchev S, Kuroiwa A, Charnay P, Krumlauf R . Hoxb-2 transcriptional activation in rhombomeres 3 and 5 requires an evolutionarily conserved cis-acting element in addition to the Krox-20 binding site. EMBO J. 1996; 15(19):5383-96. PMC: 452281. View

16.

Li X, Xiao R, Tembo K, Hao L, Xiong M, Pan S . PEG10 promotes human breast cancer cell proliferation, migration and invasion. Int J Oncol. 2016; 48(5):1933-42. DOI: 10.3892/ijo.2016.3406. View

17.

Siegel R, DeSantis C, Jemal A . Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014; 64(2):104-17. DOI: 10.3322/caac.21220. View

18.

Monje M, Borniger J, DSilva N, Deneen B, Dirks P, Fattahi F . Roadmap for the Emerging Field of Cancer Neuroscience. Cell. 2020; 181(2):219-222. PMC: 7286095. DOI: 10.1016/j.cell.2020.03.034. View

19.

Saloman J, Albers K, Rhim A, Davis B . Can Stopping Nerves, Stop Cancer?. Trends Neurosci. 2016; 39(12):880-889. PMC: 5148708. DOI: 10.1016/j.tins.2016.10.002. View

20.

Kazerounian S, Yee K, Lawler J . Thrombospondins in cancer. Cell Mol Life Sci. 2008; 65(5):700-12. PMC: 2752021. DOI: 10.1007/s00018-007-7486-z. View