The Cargo Protein MAP17 (PDZK1IP1) Regulates the Cancer Stem Cell Pool Activating the Notch Pathway by Abducting NUMB.
Purpose:Cancer stem cells (CSC) are self-renewing tumor cells, with the ability to generate diverse differentiated tumor cell subpopulations. They differ from normal stem cells in the deregulation of the mechanisms that normally control stem cell physiology. CSCs are the origin of metastasis and highly resistant to therapy. Therefore, the understanding of the CSC origin and deregulated pathways is important for tumor control.Experimental Design:We have included experimentsin vitro, in cell lines and tumors of different origins. We have used patient-derived xenografts (PDX) and public transcriptomic databases of human tumors.Results:MAP17 (PDZKIP1), a small cargo protein overexpressed in tumors, interacts with NUMB through the PDZ-binding domain activating the Notch pathway, leading to an increase in stem cell factors and cancer-initiating-like cells. Identical behavior was mimicked by inhibiting NUMB. Conversely, MAP17 downregulation in a tumor cell line constitutively expressing this gene led to Notch pathway inactivation and a marked reduction of stemness. In PDX models, MAP17 levels directly correlated with tumorsphere formation capability. Finally, in human colon, breast, or lung there is a strong correlation of MAP17 expression with a signature of Notch and stem cell genes.Conclusions:MAP17 overexpression activates Notch pathway by sequestering NUMB. High levels of MAP17 correlated with tumorsphere formation and Notch and Stem gene transcription. Its direct modification causes direct alteration of tumorsphere number and Notch and Stem pathway transcription. This defines a new mechanism of Notch pathway activation and Stem cell pool increase that may be active in a large percentage of tumors.Clin Cancer Res; 23(14); 3871-83. ©2017 AACR.
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.|Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain.|CIBER de Cancer, Seville, Spain.
Jose Manuel
JM
Garcia-Heredia
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.|CIBER de Cancer, Seville, Spain.
Antonio
A
Lucena-Cacace
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.|CIBER de Cancer, Seville, Spain.
Eva M
EM
Verdugo-Sivianes
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.|CIBER de Cancer, Seville, Spain.
Marco
M
Pérez
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain. acarnero-ibis@us.es.|CIBER de Cancer, Seville, Spain.
Amancio
A
Carnero
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C509768:PDZK1IP1 protein, human; D051880:Receptors, Notch