Albert Santamaria‐Martínez

École Polytechnique Fédérale de Lausanne

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Joerg Huelsken

École Polytechnique Fédérale de Lausanne

Giovanni Ciriello

University of Lausanne

Daniele Tavernari

University of Lausanne

Marco Varrone

Swiss Cancer Center Léman

Elisa Oricchio

École Polytechnique Fédérale de Lausanne

Antoni Hurtado

Centro de Investigación del Cáncer

Dina Milowich

Hôpital du Valais

Divyanshu Srivastava

École Polytechnique Fédérale de Lausanne

Anna Barbosa-Desongles

Universitat Autònoma de Barcelona

Tomàs Pinós

Vall d'Hebron Institut de Recerca

Cooperative Institutions

École Polytechnique Fédérale de Lausanne

University of Lausanne

Swiss Cancer Center Léman

University Hospital of Lausanne

SIB Swiss Institute of Bioinformatics

Universitat Autònoma de Barcelona

Vall d'Hebron Institut de Recerca

Ludwig Cancer Research

KU Leuven

University of Fribourg

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CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity

Nature Genetics (2023)

Marco Varrone Daniele Tavernari Albert Santamaria‐Martínez Logan A. Walsh Giovanni Ciriello

10.1038/s41588-023-01588-4

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Citations (39)

Breast Cancer Stem Cells with Tumor- versus Metastasis-Initiating Capacities Are Modulated by TGFBR1 Inhibition

Stem Cell Reports (2019)

Flavia Fico Mélanie Bousquenaud Curzio Rüegg Albert Santamaria‐Martínez

Cancer stem cells (CSCs) are defined by their ability to regenerate a tumor upon transplantation. However, it is not yet clear whether tumors contain a single CSC population or different subsets of cells with mixed capacities for initiating primary and secondary tumors. Using two different identification strategies, we studied the overlap between metastatic stem cells and tumor-initiating cells (TICs) in the MMTV-PyMT model. Our results show that in the MMTV-PyMT model, Lin−CD90−ALDHhigh cells retained a high tumor-initiating potential (TIP) in orthotopic transplants, in contrast to Lin−CD24+CD90+, which retained higher metastatic capacity. Interestingly, suppression of TGFβ signaling increased TIC numbers. We here describe the existence of distinct populations of CSCs with differing capacities to initiate tumors in the primary or the secondary site. Inhibiting TGFβ signaling shifts the balance toward the former, which may have unanticipated implications for the therapeutic use of TGFβ/TGFBR1 inhibitors.

CD90

CD24

Tumor initiation

10.1016/j.stemcr.2019.05.026

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The niche under siege: novel targets for metastasis therapy

Journal of Internal Medicine (2013)

Albert Santamaria‐Martínez Joerg Huelsken

Metastasis is an inefficient process and most cancer cells fail to colonize secondary sites. There are several possible reasons for this. First, the nature of the infiltrating cells is important as a small population of cancer stem cells has been shown to have exclusive metastasis-initiating potential. Secondly, supportive niches are required to promote the outgrowth of disseminated tumour cells. Such niches are either produced prior to the arrival of cancer cells in the target organ or are induced ad hoc upon cell infiltration. Components of the extracellular matrix (ECM) have been found to play a role in establishing these niches. This has highlighted the importance of the ECM for metastatic progression, and suggests that such components may provide alternative targets for treatment of metastatic disease.

Infiltration (HVAC)

10.1111/joim.12024

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Citations (19)

CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Marco Varrone Daniele Tavernari Albert Santamaria‐Martínez Logan A. Walsh Giovanni Ciriello

ABSTRACT Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophils and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.

10.1101/2023.01.10.523386

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Human SHBG mRNA Translation Is Modulated by Alternative 5′-Non-Coding Exons 1A and 1B

PLoS ONE (2010)

Tomàs Pinós Anna Barbosa-Desongles Antoni Hurtado Albert Santamaria‐Martínez Inés de Torres

The human sex hormone-binding globulin (SHBG) gene comprises at least 6 different transcription units (TU-1, -1A, -1B, -1C, -1D and -1E), and is regulated by no less than 6 different promoters. The best characterized are TU-1 and TU-1A: TU-1 is responsible for producing plasma SHBG, while TU-1A is transcribed and translated in the testis. Transcription of the recently described TU-1B, -1C, and -1D has been demonstrated in human prostate tissue and prostate cancer cell lines, as well as in other human cell lines such as HeLa, HepG2, HeK 293, CW 9019 and imr 32. However, there are no reported data demonstrating their translation. In the present study, we aimed to determine whether TU-1A and TU-1B are indeed translated in the human prostate and whether 5' UTR exons 1A and 1B differently regulate SHBG translation.Cis-regulatory elements that could potentially regulate translation were identified within the 5'UTRs of SHBG TU-1A and TU-1B. Although full-length SHBG TU-1A and TU-1B mRNAs were present in prostate cancer cell lines, the endogenous SHBG protein was not detected by western blot in any of them. LNCaP prostate cancer cells transfected with several SHBG constructs containing exons 2 to 8 but lacking the 5'UTR sequence did show SHBG translation, whereas inclusion of the 5'UTR sequences of either exon 1A or 1B caused a dramatic decrease in SHBG protein levels. The molecular weight of SHBG did not vary between cells transfected with constructs with or without the 5'UTR sequence, thus confirming that the first in-frame ATG of exon 2 is the translation start site of TU-1A and TU-1B.The use of alternative SHBG first exons 1A and 1B differentially inhibits translation from the ATG situated in exon 2, which codes for methionine 30 of transcripts that begin with the exon 1 sequence.

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10.1371/journal.pone.0013844

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Citations (3)

Lymphoma tissue fragments to anticipate response to targeted therapies

Zenodo (CERN European Organization for Nuclear Research) (2022)

Albert Santamaria‐Martínez Justine Epiney Divyanshu Srivastava Daniele Tavernari Marco Varrone

10.5281/zenodo.7447771

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Estrogen receptor beta displays cell cycle-dependent expression and regulates the G1 phase through a non-genomic mechanism in prostate carcinoma cells.

DOAJ (DOAJ: Directory of Open Access Journals) (2008)

Antoni Hurtado Tomàs Pinós Anna Barbosa-Desongles Sandra López-Avilés Jordi Barquinero

It is well known that estrogens regulate cell cycle progression, but the specific contributions and mechanisms of action of the estrogen receptor beta (ERbeta) remain elusive.We have analyzed the levels of ERbeta1 and ERbeta2 throughout the cell cycle, as well as the mechanisms of action and the consequences of the over-expression of ERbeta1 in the human prostate cancer LNCaP cell line.Both ERbeta1 mRNA and protein expression increased from the G1 to the S phase and decreased before entering the G2/M phase, whereas ERbeta2 levels decreased during the S phase and increased in the G2/M phase. ERbeta1 protein was detected in both the nuclear and non-nuclear fractions, and ERbeta2 was found exclusively in the nucleus. Regarding the mechanisms of action, endogenous ERbeta was able to activate transcription via ERE during the S phase in a ligand-dependent manner, whereas no changes in AP1 and NFkappaB transactivation were observed after exposure to estradiol or the specific inhibitor ICI 182,780. Over-expression of either wild type ERbeta1 or ERbeta1 mutated in the DNA-binding domain caused an arrest in early G1. This arrest was accompanied by the interaction of over-expressed ERbeta1 with c-Jun N-terminal protein kinase 1 (JNK1) and a decrease in c-Jun phosphorylation and cyclin D1 expression. The administration of ICI impeded the JNK1-ERbeta1 interaction, increased c-Jun phosphorylation and cyclin D1 expression and allowed the cells to progress to late G1, where they became arrested.Our results demonstrate that, in LNCaP prostate cancer cells, both ERbeta isoforms are differentially expressed during the cell cycle and that ERbeta regulates the G1 phase by a non-genomic mechanism.

AP-1 transcription factor

10.3233/clo-2008-0430

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Citations (23)

Identificació, aïllament i caracterització de cèl·lules mare en models de càncer de pròstata

TDX (Tesis Doctorals en Xarxa) (2009)

Albert Santamaria‐Martínez

El cancer de prostata es un tipus de cancer de creixement lent, estructura heterogenia, etiologia desconeguda diagnosticat generalment en homes d'edat avancada (>50 anys). Excloent el cancer de pell no melanocitic, es el tumor mes frequent (19,6%) en els homes a Catalunya. De manera natural evoluciona cap a la independencia hormonal, tot i que es creu que aquesta transicio es accelerada pel tractament amb antiandrogens. La interaccio entre estroma i epiteli es d'una gran importancia per a l'evolucio del tumor.El concepte de cel·lula mare cancerosa fa referencia a una suposada poblacio cel·lular tumoral, amb caracteristiques analogues a les de les cel·lules mare normals, responsable de la generacio i manteniment tumorals. La side population (SP), es un conjunt de cel·lules discriminat per citometria de flux amb capacitat per bombejar certes drogues, xenobiotics, hormones i altres compostos, que s'ha vist que esta enriquida en cel·lules mare en alguns sistemes.En aquest treball es va proposar de trobar cel·lules mare canceroses basicament en dos models de cancer de prostata diferents: les linies cel·lulars LNCaP i PC-3 i el model animal PAC-120 (xenotrasplantament d'adenocarcinoma hormonodependent que recapitula de manera fiable el cancer de prostata). Per tal d'assolir el primer objectiu d'identificar-les, es va proposar l'assaig de side population, per tal i com s'ha demostrat la seva validesa per aillar poblacions enriquides en cel·lules mare i es un assaig que dona informacio funcional sobre les cel·lules i en mante la seva viabilitat. A mes, aquesta tecnica permetia tambe assolir el segon objectiu i parcialment el tercer, es a dir aillarles i caracteritzar-les.Partint de la hipotesi nul·la que hi ha cel·lules amb caracteristiques de cel·lules mare al cancer de prostata, els objectius d'aquesta tesi per punts han estat:1. Identificar i aillar cel·lules de la side population tant als tumors del PAC-120 com a les linies cel·lulars LNCaP i PC-3.2. Caracteritzar els perfils genics de les cel·lules de la side population aillades.3. Comprovar la seva naturalesa progenitora mitjancant assaigs de diferenciacio in Vitro o de tumorigenesi in vivo.4. Analitzar l'existencia de cel·lules tumorals disseminades al moll d'os del model PAC-120 i estudiar la seva possible naturalesa progenitora.Els resultats d'aquest treball demostren que el tumor del model PAC-120, format per una barreja d'epiteli huma i estroma muri, conte cel·lules de la side population i que els cultius del tumor PAC-120 tambe contenen cel·lules de la side population. La separacio i analisi clonal de les cel·lules de la side population dels cultius revelen que aquestes tenen una capacitat variable de donar lloc a cel·lules de la side population. A mes, l'estudi dels perfils genics d'aquestes cel·lules, la seva expressio proteica (immunofenotip Cd45- Sca-1+ Cd81+), la seva adherencia al plastic, la seva morfologia fibroblastoide, la seva gran capacitat proliferativa i la seva capacitat de diferenciacio revelen que son cel·lules multipotents estromals. Per tant, el tumor PAC-120 conte cel·lules multipotents estromals que poden ser aillades mitjancant l'assaig de la side population. Aixi mateix, el fenotip SP d'aquestes cel·lules esta associat amb el seu estat de diferenciacio, ja que la seva diferenciacio en comporta la perdua.D'altra banda, s'ha demostrat que les cel·lules multipotents estromals aillades secreten TGF-beta de manera autocrina i tenen la via del TGF-beta activa. El TGF-beta mante la proliferacio i inhibeix la diferenciacio de les cel·lules multipotents estromals obtingudes del tumor.Quant a les linies, en aquest treball s'ha demostrat que tant LNCaP i PC-3 contenen cel·lules de la side population, i presenten RNA i proteina del transportador ABCG2. El promotor d'ABCG2 esta parcialment desmetilat a la linia cel·lular LNCaP i molt metilat a PC-3. L'addicio del composta bloquejador de la metilacio de novo 5-aza afavoreix la desmetilacio del promotor d'ABCG2, la transcripcio del gen, la traduccio de la proteina i l'augment de la side population. A mes, el serum i l'estradiol regulen a l'alca la transcripcio d'ABCG2 i, en el cas del serum, tambe de la side population a la linia cel·lular LNCaP.

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Identification of multipotent mesenchymal stromal cells in the reactive stroma of a prostate cancer xenograft by side population analysis

Experimental Cell Research (2009)

Albert Santamaria‐Martínez Jordi Barquinero Anna Barbosa-Desongles Antoni Hurtado Tomàs Pinós

10.1016/j.yexcr.2009.05.007

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Citations (31)

TGFBI modulates tumour hypoxia and promotes breast cancer metastasis

Molecular Oncology (2020)

Flavia Fico Albert Santamaria‐Martínez

Breast cancer metastasis is a complex process that depends not only on intrinsic characteristics of metastatic stem cells, but also on the particular microenvironment that supports their growth and modulates the plasticity of the system. In search for microenvironmental factors supporting cancer stem cell (CSC) growth and tumour progression to metastasis, we here investigated the role of the matricellular protein transforming growth factor beta induced (TGFBI) in breast cancer. We crossed the MMTV-PyMT model of mammary gland tumorigenesis with a TgfbiΔ/Δ mouse and studied the CSC content of the tumours. We performed RNAseq on wt and ko tumours, and analysed the tumour vasculature and the immune compartment by IHC and FACS. The source of TGFBI expression was determined by qPCR and by bone marrow transplantation experiments. Finally, we performed in silico analyses using the METABRIC cohort to assess the potential prognostic value of TGFBI. We observed that deletion of Tgfbi led to a dramatic decrease in CSC content and lung metastasis. Our results show that lack of TGFBI resulted in tumour vessel normalisation, with improved vessel perfusion and decreased hypoxia, a major factor controlling CSCs and metastasis. Furthermore, human data mining in a cohort of breast cancer patients showed that higher expression of TGFBI correlates with poor prognosis and is associated with the more aggressive subtypes of breast cancer. Overall, these data reveal a novel biological mechanism controlling metastasis that could potentially be exploited to improve the efficacy and delivery of chemotherapeutic agents in breast cancer.

TGFBI

10.1002/1878-0261.12828

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Citations (47)