PMID- 28533307 OWN - NLM STAT- MEDLINE DCOM- 20170817 LR - 20210202 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 130 IP - 4 DP - 2017 Jul 27 TI - SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma. PG - 501-513 LID - 10.1182/blood-2017-04-776740 [doi] AB - SOX11 overexpression in mantle cell lymphoma (MCL) has been associated with more aggressive behavior and worse outcome. However, SOX11 oncogenic pathways driving MCL tumor progression are poorly understood. Here, we demonstrate that SOX11 binds to regulatory regions of 2 important genes for microenvironment signals in cancer: (C-X-C motif) chemokine receptor 4 (CXCR4) and PTK2 (encoding for focal adhesion kinase [FAK]). Moreover, SOX11(+) xenograft and human primary MCL tumors overexpress cell migration and stromal stimulation gene signatures compared with their SOX11(-) counterparts. We show that SOX11 directly upregulates CXCR4 and FAK expression, activating PI3K/AKT and ERK1/2 FAK-downstream pathways in MCL. Concordantly, SOX11(+) MCL cells have higher cell migration, transmigration through endothelial cells, adhesion to stromal cells, and cell proliferation and display an increased resistance to conventional drug therapies compared with SOX11(-) MCL cells. Specific FAK inhibition blocks downstream PI3K/AKT- and ERK1/2-mediated phosphorylation. Additionally, specific FAK and PI3K inhibitors reduce SOX11-enhanced MCL cell migration and stromal interactions and revert cell adhesion-mediated drug resistance (CAM-DR) to the same levels as SOX11(-) MCL cells. In intravenous MCL xenograft models, SOX11(+) MCL cells display higher cell migration, invasion, and growth compared with SOX11-knockdown cells, and specific FAK and CXCR4 inhibitors impair SOX11-enhanced MCL engraftment in bone marrow. Overall, our results suggest that SOX11 promotes MCL homing and invasion and increases CAM-DR through the direct regulation of CXCR4 and FAK expression and FAK/PI3K/AKT pathway activation, contributing to a more aggressive phenotype. Inhibition of this pathway may represent an efficient strategy to overcome stromal-mediated chemotherapy refractoriness in aggressive MCL. CI - (c) 2017 by The American Society of Hematology. FAU - Balsas, Patricia AU - Balsas P AUID- ORCID: 0000-0002-9485-9179 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC); and. FAU - Palomero, Jara AU - Palomero J AUID- ORCID: 0000-0002-2092-2526 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. FAU - Eguileor, Alvaro AU - Eguileor A AUID- ORCID: 0000-0002-0302-6762 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC); and. FAU - Rodriguez, Marta Leonor AU - Rodriguez ML AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. FAU - Vegliante, Maria Carmela AU - Vegliante MC AUID- ORCID: 0000-0002-3165-1768 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. FAU - Planas-Rigol, Ester AU - Planas-Rigol E AUID- ORCID: 0000-0001-5948-2241 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Vasculitis Research Unit, Department of Autoimmune Diseases and. FAU - Sureda-Gomez, Marta AU - Sureda-Gomez M AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. FAU - Cid, Maria C AU - Cid MC AUID- ORCID: 0000-0002-4730-0938 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Vasculitis Research Unit, Department of Autoimmune Diseases and. FAU - Campo, Elias AU - Campo E AUID- ORCID: 0000-0001-9850-9793 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC); and. AD - Department of Anatomic Pathology, Hospital Clinic, University of Barcelona, Barcelona, Spain. FAU - Amador, Virginia AU - Amador V AUID- ORCID: 0000-0002-3016-2874 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC); and. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170522 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (CCR4 protein, human) RN - 0 (Receptors, CCR4) RN - 0 (SOX11 protein, human) RN - 0 (SOXC Transcription Factors) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.2 (Focal Adhesion Kinase 1) RN - EC 2.7.10.2 (PTK2 protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM CIN - Blood. 2017 Jul 27;130(4):389-391. PMID: 28751356 MH - Animals MH - Cell Line, Tumor MH - Focal Adhesion Kinase 1/genetics/*metabolism MH - HEK293 Cells MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Lymphoma, Mantle-Cell/genetics/*metabolism/pathology MH - Mice MH - Mice, SCID MH - Neoplasm Invasiveness MH - Phosphatidylinositol 3-Kinases/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Receptors, CCR4/genetics/*metabolism MH - SOXC Transcription Factors/genetics/*metabolism MH - *Signal Transduction MH - *Tumor Microenvironment EDAT- 2017/05/24 06:00 MHDA- 2017/08/18 06:00 CRDT- 2017/05/24 06:00 PHST- 2017/04/05 00:00 [received] PHST- 2017/05/16 00:00 [accepted] PHST- 2017/05/24 06:00 [pubmed] PHST- 2017/08/18 06:00 [medline] PHST- 2017/05/24 06:00 [entrez] AID - S0006-4971(20)33164-5 [pii] AID - 10.1182/blood-2017-04-776740 [doi] PST - ppublish SO - Blood. 2017 Jul 27;130(4):501-513. doi: 10.1182/blood-2017-04-776740. Epub 2017 May 22.