RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis

RESUME RANK signaling is essential for mammary gland development and progesterone induced tumorigenesis. Here we show that RANK controls mammary stem cell fate; increased RANK signaling results in accumulation of stem and progenitor cells leading to spontaneous tumor formation. RANK signaling interf...

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Bibliographic Details
Author: Pellegrini, Pasquale
Format: doctoral thesis
Status:Published version
Publication Date:2014
Country:España
Institution:CBUC, CESCA
Repository:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/586316
Online Access:http://hdl.handle.net/10803/586316
Access Level:Open access
Keyword:RANK
RANKL
Mammary gland
Breast cancer
Stem cell
Metastasis
Glándula mamaria
Cancer de mama
Célula progenitora
616
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oai_identifier_str oai:www.tdx.cat:10803/586316
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spelling RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasisPellegrini, PasqualeRANKRANKLMammary glandBreast cancerStem cellMetastasisGlándula mamariaCancer de mamaCélula progenitora616RESUME RANK signaling is essential for mammary gland development and progesterone induced tumorigenesis. Here we show that RANK controls mammary stem cell fate; increased RANK signaling results in accumulation of stem and progenitor cells leading to spontaneous tumor formation. RANK signaling interferes with alveolar commitment through depletion of CD61+ alveolar progenitors and regulation of Elf-5/STAT5 pathway. Using pharmacological and genetic approaches we show that RANK signaling promotes tumor initiation, progression and metastasis in spontaneous breast cancer models and expands tumor initiating cells and metastasis initiating cells. RANK pathway mediates the crosstalk between tumor cells and their microenvironment modulating the tumor immune response. RANK expression correlates with aggressiveness and metastasis in human tumors. Altogether our data support that RANK signaling could be a novel therapeutic target in breast cancer.RESUMEN La vía de RANK es esencial para el desarollo de la glándula mamaria y la tumorigénesis inducida por progesterona. Demostramos que RANK controla la especificación de linajes mamarios, y que un aumento de señalización a través de RANK induce una acumulación de células madre y progenitoras de mama con la consiguiente formación espontánea de tumores. RANK bloquea la diferenciación alveolar a través de la disminución de progenitoras alveolares CD61+ y la regulación de la via Elf-5/STAT5. Utilizando estrategias genéticas y farmacológicas demostramos que RANK promueve la formación, progresión tumoral y la metástasis de modelos de tumorigenesis espontánea de mama, y expande las poblaciones de células iniciadoras de tumores y células iniciadoras de metastasis. La vía de RANK media además la interacción entre las células tumorales y su entorno, modulando la respuesta inmune tumoral. El aumento en la expresión de RANK se correlaciona con la agresividad de tumores humanos y la metástasis. Estos resultados sugieren que la vía de RANK puede ser una nueva diana terapéutica en cáncer de mama.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraGonzález Suárez, EvaUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut201820182014info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion190 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/586316TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/5863162026-06-14T12:46:07Z
dc.title.none.fl_str_mv RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
title RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
spellingShingle RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
Pellegrini, Pasquale
RANK
RANKL
Mammary gland
Breast cancer
Stem cell
Metastasis
Glándula mamaria
Cancer de mama
Célula progenitora
616
title_short RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
title_full RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
title_fullStr RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
title_full_unstemmed RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
title_sort RANK signaling, a master regulator of mammary stemness and cancer : characterization of RANK and RANKL pathway stem cell fate, tumorigenesis and metastasis
dc.creator.none.fl_str_mv Pellegrini, Pasquale
author Pellegrini, Pasquale
author_facet Pellegrini, Pasquale
author_role author
dc.contributor.none.fl_str_mv González Suárez, Eva
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv RANK
RANKL
Mammary gland
Breast cancer
Stem cell
Metastasis
Glándula mamaria
Cancer de mama
Célula progenitora
616
topic RANK
RANKL
Mammary gland
Breast cancer
Stem cell
Metastasis
Glándula mamaria
Cancer de mama
Célula progenitora
616
description RESUME RANK signaling is essential for mammary gland development and progesterone induced tumorigenesis. Here we show that RANK controls mammary stem cell fate; increased RANK signaling results in accumulation of stem and progenitor cells leading to spontaneous tumor formation. RANK signaling interferes with alveolar commitment through depletion of CD61+ alveolar progenitors and regulation of Elf-5/STAT5 pathway. Using pharmacological and genetic approaches we show that RANK signaling promotes tumor initiation, progression and metastasis in spontaneous breast cancer models and expands tumor initiating cells and metastasis initiating cells. RANK pathway mediates the crosstalk between tumor cells and their microenvironment modulating the tumor immune response. RANK expression correlates with aggressiveness and metastasis in human tumors. Altogether our data support that RANK signaling could be a novel therapeutic target in breast cancer.
publishDate 2014
dc.date.none.fl_str_mv 2014
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/586316
url http://hdl.handle.net/10803/586316
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 190 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405470598365184
score 15.301629

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