Once the tumor metastasizes to bone, the metastatic disease become incurable and current therapies are palliative. Thus, to better understand the biology of PC bone metastasis and to investigate new therapeutic options it is crucial to develop new animal models.

We have established new experimental models of PC bone metastasis by inoculation (intratibial and intracardiac) of human PC cell lines in immunodeficient mice to make a suitable model for evaluating novel compounds as future therapeutic approaches. Extensive bone metastases were monitored by in vivo bioluminescence imaging. By applying different strategies we have described new molecular targets involved in the mechanisms of PC bone metastasis.

1) Garcia M, et al. BJU Int. 2014;113:E164-77.

2) Doll A, et al. Arch Esp Urol. 2013;66:463-74.

Principal Investigator

Anna Santamaría Margalef, PhD

Clinical Associated Researchers

Juan Morote Robles, MD, PhD (co-head Biomedical Research Group in Urology)

Jacques Planas, MD, PhD  

PhD Students

Letícia Suárez

Marta Barber

Technician

Adrián García

Past members

Dr. Núria Masiá

Dr. Melissa Bradbury (MD)

Dr. Alfonso Parrilla

Dr. Mireia Oliván

Dr. Blanca Majem

Gabriel Tamayo

BACKGROUND

The efforts of our team are devoted to give answer to the main challenges in the field of cancer (diagnosis, prognosis and therapy), in particular we focus our attention to homone-dependent tumors, namely prostate tumors (but not limited to) and on cell cycle-related signaling pathways, specifically mitosis and the role of key regulatory enzymes (kinesins, kinases and ubiquitin ligases).

RESEARCH STRATEGY AND SCOPE

Alternative therapeutic strategies based on mitotic regulators: kinesins

Alterations in the expression of several mitotic regulators have been associated with tumor formation in many cancers. Recent genomic studies have shown that androgen receptor (AR) activity in hormone-refractory prostate cancer (PCa) is not identical to that displayed in androgen dependent cells. Interestingly, increasing evidence in the last years suggest that castrated-resistance prostate cancer (CRPC) cells have undergone a genetic reprogramming to upregulate the expression of M-phase cell cycle genes. AR selectively and directly upregulates a set of mitotic regulators to promote androgen independent PCa. Enrichment of M-phase proteins and pathways has been found in CRPC chemotherapy-resistant tumors compared with their chemotherapy-naïve counterparts. In this context, the main goal of this research line is to gain novel molecular insights into the progression of PCa, with special emphasis on the involvement of mitotic regulators in the acquisition of prostate tumors androgen independence. Through a proteomic-based approach we have identified drivers of the castration-resistant disease and several mitotic kinesins stand out. We aim at studying their role as potential as therapeutic targets.

Contribution to disfunctionality of mitotic regulators alterations to CIN in certain tumors

We aim at understanding first, the basic molecular mechanisms by which mitotic players (spindle-associated proteins and mitotic kinases such us hBora, Ska, CHICA, Plk1, Aurora A) that normally operate to ensure the error-free segregation of chromosomes, and how are they regulated in time and space and second, and which mechanisms give rise to the chromosomal instability that is typical of tumor cells by taking advantage of the animal and human models of cancer currently used in the laboratory.

BRCA1 and BRCA2-dependent ubiquitination and phosphorylation landscapes in cancer patients

High-grade serous carcinoma (HGSC) is characterized by presenting defects in the homologous recombination repair, most frequently associated to BRCA1 mutations. Although most patients will initially respond to first-line chemotherapy with platinum-based agents, up to a quarter will be resistant to treatment. In recent years we have advanced in the understanding of HGSC tumour physiology and its dependence on BRCA1 and, secondly, have identified protein signature able to discriminate between chemotherapy resistant and sensitive patients. In collaboration with the clinicians at the Gynecology Department at the Vall Hebron Hospital, we have performed a multi-layered proteomic characterization of patient-derived ovarian tissues, which has revealed the importance of both ubiquitination and phosphorylation layers of regulation in modulating key cellular processes in HGSC, their dependency on BRCA1 and the identification of BRCA1 substrates responsible for driving ubiquitination signalling. Also, using discovery and targeted proteomics in HGSC tissues, we have identified a protein signature able to discriminate between chemotherapy resistant and sensitive patients at the time of cancer diagnosis. Collectively, we have performed a comprehensive molecular characterization of HGSC that provides a groundwork for future mechanistic-based studies and the development of new targeted therapies in ovarian cancer. In addition, we advance in the optimization of therapeutic decision making through the identification of a promising protein signature able to predict response to chemotherapy.

On the other hand, previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with mCRPC. Although BRCA2 mutations are known to confer an increased risk of breast and ovarian cancer, recent observations have shown that alterations of BRCA2 are more prevalent than previously appreciated in men with PCa and more frequent than alterations in any other DDR gene. We aim at translating our expertise and results on BRCA1 related to HGSC, to get deeper insights into the functional relevance of BRCA2 mutations in PCa. In close collaboration with the Urology Deparment at Vall Hebron (Dr. Jacques Planas), we also aim at improving the management of patients with BRCA2 mutations.

Drug development

We are interested in testing the therapeutic potential of new synthetic or natural compounds in clinically representative tumor cell lines (of prostate and ovarian cancer) and preclinical mouse models to improve the efficacy and safety of currently available treatments. 

ONGOING and PAST COMPETITIVE PROJECTS:

1. 2019PROD00087, SalivOmiX: Prova basada en la detecció de miRNAs en saliva per el diagnòstic precoç del càncer d'ovari  AGENCIA DE GESTIO D'AJUTS UNIVERSITARIS I DE RECERCA. Producte.  Anna Santamaria Margalef.  (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 01/07/2020-31/12/2021. 100.000 €.

2. PI18/01017,  SalivOmiX: Test basado en el análisis de miRNAs en saliva para la detección precoz del cáncer de ovario   Instituto de Salud Carlos III (FIS). (INSTITUTO DE INVESTIGACION HOSPITAL UNIVERSITARIO VALLE DE HEBRON).  01/2019- 12/2021. 159.720 €. Investigador principal.

3. 2017 SGR 1661,  Grup de Recerca Biomèdica en Ginecologia  AGENCIA DE GESTIO D'AJUTS UNIVERSITARIS I DE RECERCA. SGR.  Anronio Gil Moreno.  (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON).  01/01/2018- 31/12/2020. 33.000 €. Miembro de equipo.

4. AECC/2017/SANTAMARIA,  Nuevos enfoques terapéuticos para el cáncer de próstata hormono-refractario basados en la kinesina KIF11   Asociación Española Contra el Cáncer. AECC - Junta Barcelona (Conveni ajudes per a la investigació 2017).  Anna Santamaria Margalef. (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 2018-2019. 34.700 €. Investigador principal.

5. 2016 LLAV 00056, Salivomics: identification of genòmic markers to improve early ovarian càncer detection   AGENCIA DE GESTIO D'AJUTS UNIVERSITARIS I DE RECERCA. Llavor. Anna Santamaria Margalef. (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 2017-2018. 20.000 €. Investigador principal.

6. PI15/02238, Sensibilidad a quimioterapia en cáncer de ovario: Plk1 y Aurora A quinasas como terapia alternativa que permitan mejorar la respuesta antitumoral y la estratificación de pacientes  FIS. Anna Santamaria Margalef. (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 2016-2018. 122.815 €. Investigador principal.

7. RTC-2015-3821-1,  Desarrollo de nuevas aproximaciones en el manejo individualizado de pacientes con cáncer ginecológico (PredicareGYN)   Ministerio de Economía y Competitividad. RETOS.  Anna Santamaria Margalef.  (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 2015-2018. 348,6 €. Co-Investigador principal.

8. Transcripció, traducció i mitosi en càncer de pròstata resistent a teràpia.TRAMIT-CAP (GRE)   AGENCIA DE GESTIO D'AJUTS UNIVERSITARIS I DE RECERCA. Grup de Recerca Emergent (SGR-AGAUR). Anna Santamaria Margalef. (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 01/01/2014-31/12/2016. 16.000 €. Co-Investigador principal.

9. CP13/00158,  Characterization of Plk1 alterations and consequences in the progression tumorigenesis, with a focus in prostate cancer   Miguel Servet (FIS).  Anna Santamaria Margalef.  (FUNDACIO INSTITUT DE RECERCA DE L'HOSPITAL UNIV. VALL D'HEBRON). 2014-2016. 120.500 €. Investigador principal.

10. Control of chromosome segregation fidelity   Swiss Cancer League. Anna Santamaria Margalef.  (Biozentrum - University of Basel).  02/2011-02/2014.  160.000  €.  Investigador principal.

ACTIVE COLLABORATIONS WITH BIOTECH COMPANIES:

Atrys (Madrid, Spain)

Oncostellae (Santiago de Compostela, Spain)

4SC (Münich, Germany)

SELECTED PUBLICATIONS (last 5 years)

Currently under review:

- Bradbury M; … Gil-Moreno A; Sabidó E*; Santamaria, A*. BRCA1 mutations reshape the signaling landscape in high-grade serous ovarian cancer patients. Science Signalling (under review) (*equal contribution).

- Bradbury M; … Gil-Moreno A; Santamaria, A*; Sabidó E*. Molecular advances for the management of high-grade serous ovarian cancer patients. Cancers (under review) (*equal contribution).

1.- Alfonso Parrilla; Marta Barber; Blanca Majem; et al.,; Miguel F Segura; Antonio Gil Moreno; Anna Santamaria. Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer. Cancers (Basel). 12 - 4, pp. pii:E886. 06/04/2020. DOI: 10.3390/cancers12040886.

2.- Blanca Majem; Alfonso Parrilla; et al.,; Antonio Gil Moreno; Miguel F Segura; Anna Santamaría. MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways. Oncogene. 38 - 32, pp. 6035 - 6050. 08/2019. ISSN 1476-5594 DOI: 10.1038/s41388-019-0860-0

3.- Soriano A; Masanas M; Boloix A; et al; Santamaria A; Segura MF. 2019. Functional high-throughput screening reveals miR-323a-5p and miR-342-5p as a new tumour-suppressive microRNAs in neuroblastoma. Cell Mol Life Sci. 76-11, pp.2231-2243. ISSN 2041-1723.

4.- Óscar Rapado-González, Blanca Majem, et al., Anna Santamaría, Rafael López-López, Laura Muinelo-Romay, María Mercedes Suarez-Cunqueiro. A Novel Saliva-Based miRNA Signature for Colorectal Cancer Diagnosis. J. Clin. Med. 2019, 8, 2029;doi:10.3390/jcm8122029

5.- Óscar Rapado-González, Blanca Majem, Laura Muinelo-Romay, Ana Álvarez-Castro, Anna Santamaría , Antonio Gil-Moreno , Rafael López-López , María Mercedes Suárez-Cunqueiro.  Human salivary microRNAs in Cancer. J Cancer.  2018 Jan 6;9(4):638-649. doi: 10.7150/jca.21180. eCollection 2018.

6.-Devis, L; Moiola, C; Masia, N; et al; Santamaria, A; Colas, E. 2017. Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration, invasion and metastasis in early stage endometrioid endometrial cáncer. Journal of Pathology. WILEY-BLACKWELL. 241-4, pp.475-487. ISSN 0022-3417.

7.- A Almazán-Moga, P Zarzosa, C Molist, P Velasco , J Pyczek, K Simon-Keller, I Giralt, I Vidal, N Navarro, M F Segura, A Soriano, S Navarro, O M Tirado, J C Ferreres, A Santamaria, R Rota, H Hahn, J Sánchez de Toledo , J Roma, S Gallego. 2017. Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands. Br J Cancer. 117-9, pp.1314-1325. ISSN 0007-0920. 1

8.- Redli, PM; Gasic, I; Meraldi, P; Nigg, EA; Santamaria, A. The Ska complex promotes Aurora B activity to ensure chromosome biorientation. Journal of Cell Biology. 215 - 1, pp. 77 – 93, 2016. ROCKEFELLER UNIV PRESS, 10/10/2016. ISSN 0021-9525DOI: 10.1083/jcb.201603019

9.- Thomas, Y.; Cirillo, L.; Panbianco, C.; et al; Santamaria, A.; Gotta, M. 2016. Cdk1 Phosphorylates SPAT-1/Bora to Promote Plk1 Activation in C. elegans and Human Cells. Cell Reports. CELL PRESS. 15-3, pp.510-518. ISSN 2211-1247.

10.- Abad, MA; Zou, J; Medina-Pritchard, B; Nigg, EA; Rappsilber, J; Santamaria, A; Jeyaprakash, AA. 2016. Ska3 Ensures Timely Mitotic Progressionby Interacting Directly With Microtubules and Ska1 Microtubule Binding Domain. Scientific Reports. NATURE PUBLISHING GROUP. 6, pp.34042. ISSN 2045-2322.

11.- Maria-Alba* Abad; Medina, B*; Santamaria, A*; Zou, J; Plasberg-Hill, C; Madhumalar, A; Jayachandran, U; Rappsilber, J; Nigg, EA; Jeyaprakash, AA. Structural Basis for the Microtubule-Recognition by the human kinetochore Ska complex. Nature Communications. 5, pp. 2964. NATURE PUBLISHING GROUP, 2015. ISSN 2041-1723 (*equal contribution)

Prostate cancer (PC) is the second leading cause of death for cancer in men of the western Countries. While considerable advances have been made in the treatment of localized, organ-confined tumors, metastatic PC is virtually incurable and most deaths from this disease are due to the high resistance of metastasis to conventional therapies (androgen-depletion-therapy, ADT). Therefore, more precise markers for the detection of the incipient resistant tumor and more effective targets that eliminate the resistant clones are needed.

A principal aim is to identify relevant molecular pathways specifically active in aggressive prostate cancer, useful for an early detection of ADT resistant tumors and for treatment strategies.

In our studies, we have discovered the human Prostate Tumor OVerexpressed-1 (PTOV1) gene, later called Acid-2, and a second gene with a PTOV module, PTOV2, later called MED25, a component of Mediator (1-2).

The detection of PTOV1 in high-grade PIN (HGPIN) premalignant lesions is helpful to identify patients with higher probability to develop PC (3). PTOV1 ectopic expression promotes proliferation, invasion and metastasis of ADT resistant cells (1,2,4,5). PTOV1 induces the epithelial-mesenchymal-transition (EMT) and increased metastasis of PC3 cells (4). Mechanistically, PTOV1 is implicated in multiple processes controlling cell fate: it promotes mRNA translation leading to a specific increased synthesis of c-Jun and Snai1 oncogenes (4), and it is a transcriptional repressor of HES1 and HEY1 genes, leading to inhibition of Notch signalling in metastatic PC (5). PTOV1 significantly affect the self-renewal potential of the cancer stem cell populations of PC3 cells (5).  

Current objectives of our line of research are: (i) Determine the role of PTOV1 in the resistance to ADT and chemotherapy (taxols). (ii) Characterize the sub-clonal cancer stem cell populations (CSC) present in metastatic primary tumors and the genes and factors responsible for the development of the resistance to ADT.

1) Benedit P, et al. Oncogene 2001;20:1455–1464.

2) Santamaria A, et al. Am J Pathol 2003;162:897–905.

3) Morote J, et al. Clin Cancer Res 2008:14:2617-2622.

4) Marqués N, et al. Oncogene 2014;33(9):1124-34.

5) Alaña L et al., Mol Cancer 2014;13:74.

One main focus of our research is the discovery of new biomarkers for the early detection of prostate cancer (PC). The detection of proteins, RNA or miRNAs from easily accessible body fluids, such as blood or urine, will make possible to diagnose the disease at an early/pre-symptomatic stage, or monitoring responses to therapy in a simple and non-invasive way.  This will improve the specificity of the currently used PSA serum measurements.

We have identified a three-gene panel in urine able to increase the PSA specificity for the detection of PC, and using liquid chromatography, mass spectrometry and triple quadruple mass spectrometry (LC/MSMS, SRM), we have discovered the presence of specific, differential proteomic profiles in the urine of PC patients.

Furthermore, we have identified a genomic profile able to detect PC in patients previously diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN). Such profile should have an application in the clinics and improve decision making in the diagnosis and treatment of PC (Figure).

1) Sequeiros T, et al. Prostate 2015; Accepted;

2) Rigau M*, Olivan M*, et al. Int. J. Mol. Sci. 2013;14: 12620-12649;

3) Rigau M, et al. Prostate 2011; 71:1736-45;

4) Rigau M et al. Prostate 2010; 70:1760-7