Project Detail
Tackling cancer stem cells: a challenge and an opportunity to advance in anti-cancer therapy (CANCELSTEM)
 
 
Sponsor
FCT
 
Dates and Lifetime
From: 2017-01-01 To: 2021-06-30
Duration: 54 months
 
Reference
POCI-01-0145-FEDER-016390
  
 

 

Projeto nº 016390

 

Designação do projeto: Estaminalidade das células do cancro: um desafio e uma oportunidade para avançar no tratamento em Oncologia

 

Apoio à Investigação Científica e Tecnológica

 

Objetivo principal: O projeto CANCEL STEM tem como principal objetivo identificar princípios moleculares que regem a biologia das células estaminais do cancro (CSC) em vários modelos neoplásicos.

 

Região de intervenção:

 

Norte

39,99%

Centro

40,01%

Lisboa

20,00%

 

 

 

 

 

 

Entidade beneficiária:Instituto de Patologia e Imunologia Molecular (IPATIMUP/UP)

 

Instituições participantes: Instituto Nacional de Engenharia Biomédica (INEB/UP); Centro de Neurociências e Biologia Celular (CNBC/UC); Universidade de Coimbra (UC); Instituto Gulbenkian Ciência / Fundação Calouste Gulbenkian (IGC/FCG)

 


 

Data de aprovação: 04-08-2016

 

Data de início: 01-01-2017

 

Data de conclusão: 30-06-2021

 


 

Custo total elegível: 2.499.577,28€

 

Financiamento FEDER concedido: € 1.899.678,73

 

Financiamento nacional concedido: € 599.898,55

 

Entidade

Elegível

 Apoio FEDER

Apoio OE

IPATIMUP

892.526,55€

758.647,57€

133.878,98€

INEB

107.050,00€

90.992,50€

16.057,50€

IGC

500.000,78€

200.000,31€

300.000,47€

UC

194.235,94€

165.100,55€

29.135,39€

CNC

805.764,01€

684.899,41€

120.864,60€

 

 

 


 

Localização do projeto:

 

 

 


Identificação e Enquadramento do projeto:

The CANcer STEM CELl Research Programme, or CANCEL_STEM, aims to identify the molecular principles governing cancer stem cell (CSC) biology. The consortium was strategically designed to bring together researchers with complementary competences to achieve common objectives: 1) To identify tumour signalling networks and microenvironment traits that define and sustain CSC; 2) To determine how CSC arise, promote tumour evolution and home to form metastasis; 3) To develop proprietary technologies specifically targeting drug resistant CSC. As long-term goal, CSC biomarkers, signatures and therapeutic targets will be further clinically exploited to improve cancer monitoring and treatment.

The programme involves top research units - i3S, CNC.IBILI and IGC, with clear synergies in terms of means and resources, where interactions between researchers performing basic, translational and applied research will be unique in Portugal. Scientific complementary skills are unequivocal, ensuring consistency of the work plan: i3S members work on oncobiology; IGC investigators work on basic aspects of cell biology; researchers from CNC.IBILI work on stem cell biology and on therapeutics development. This project is an opportunity to reinforce (foster) the interactions between these institutions, which have already established collaborative projects and share students. The multidisciplinary scientific expertise of the team, the biological reagents available, the methods and equipment accessible, and the scientific and management structure of the programme endow this network the capacity to become a reference network on CSC research.

The proposal is relevant in a critical health problem - Cancer, and innovative in the SCTN, focusing on an area with clear weaknesses in Portugal. CSC research has not yet been covered by the Institutes involved or by other national networks. The consortium will allow a faster breakthrough in CSC research, still fragmented, facilitating the transfer of knowledge on technologies, products and solutions that will contribute to the economic and social development of the country. The CANCEL STEM programme is integrated in the smart-specialization strategy (RIS3) for Portugal, aligned with priority domains: health; knowledge transfer to pharmaceutical industry; advanced technologies to create innovative added-value products.

 


 

Síntese do projeto:

The specific scientific goals of the CANCEL STEM Programme are to: 1) Identify mechanisms of CSC formation and properties; 2) Decipher the role of the tumour microenvironment in sustaining CSC, including cellular and non-cellular elements; 3) Disclose the contribution of CSC to the metastatic process, with a major focus on systemic circulation and colonization at distant sites; and 4) Tackle properties and mechanisms of CSC drug resistance and design novel therapies to eradicate these cancer cell populations. Concrete Working Packages (WP1-10) are proposed to achieve these general goals, which results are expected to impact on Cancer Research.

 

Working Package 1

CSC immortalization: molecular mechanisms to maintain the telomeres length

(Paula Soares, Ipatimup/i3S; Miguel Godinho, IGC)

Taking advantage of the expertise from Paula Soares (at i3S) and from Miguel G. Ferreira (at IGC), WP1 has been planned with a focus on CSC immortalization. CSC are known to mislead the intrinsic telomere length-sensing control mechanisms to accomplish a state of replicative immortalization. In fact, the molecular mechanisms responsible for preventing unrestrained cell division are thought to be completely absent in cells with a stem-like phenotype. Since the most common mechanism for telomere elongation is the use of the reverse transcriptase telomerase (TERT), it will be disclosed how the presence of TERT promoter mutations induce the acquisition of a stem-like phenotype. Moreover, as a restricted subset of cancers maintain telomeres through a repair-based mechanism, termed Alternative Lengthening of Telomeres (ALT), the WP1 team will also uncover the molecules/pathways involved and determine if ALT mechanism becomes an option to continuous proliferation upon telomerase inhibition. Thyroid and pancreatic endocrine tumours will be used as models, since TERTp mutations and ALT mechanisms are well documented in these lesions.

 

Working Package 2

CSC reprogramming: reconstructing the transcription factor network

(Raquel Almeida, Ipatimup/i3S; Filipe Pereira, CNC/UC Biotech)

In WP2, the emphasis will be given to CSC reprogramming, by studying the gene regulatory program and associated molecular signalling involved in gastric and intestinal CSC differentiation and survival. The general goal will be to find new biomarkers and new therapeutic approaches that specifically target CSC in these cancer models. The work package will be performed by Carlos F. Pereira’s team (at CNC.IBILI), which has expertise in transcription factor-mediated cellular reprogramming, stem cell biology and gene expression analysis at the single-cell level, in collaboration with Raquel Almeida’s team (at i3S), which has valuable patient-derived samples and cellular models enriched in CSC features through overexpression of the embryonic stem cell marker SOX2. The combination of their unique tools and expertise provides a great opportunity to explore the molecular pathways and potential drug targets specific of gastric and intestinal CSC.

 

Working Package 3

CSC plasticity: EMT and stem cell state generation

(Carla Oliveira, Ipatimup/i3S; Claudine Chaouiya, IGC)

Based on preliminary work produced by Carla Oliveira (at i3S) and Claudine Chaouiya (at IGC), the aim of WP3 will be to identify targets that impair CSC plasticity. Throughout frequent Epithelial-Mesenchymal-Epithelial transitions (EMT/MET) occurring in tumours, it has been found an enrichment on cancer cells with stem-like properties. Since these observations point to a link between EMT/MET, CSC and resistance to anti-neoplastic therapeutic strategies, the WP3 team will refine their EMT computational model to predict, in silico, targets to be silenced in order to impair stemness acquisition during EMT/MET. The predicted targets will be biologically validated along with their sensitivity to available therapeutic drugs.

 

Working Package 4

CSC cytoskeleton: membrane/actin interactions in the acquisition of stem cell properties in cancer

(Joana Paredes, Ipatimup/i3S; Florence Janody, IGC)

WP4 will be concentrated on outside-inside CSC communication, aiming to elucidate how the molecular complex composed by cell-cell adhesion molecules (cadherins) and the actin cytoskeleton are able to induce CSC features. Using breast cancer initiation and progression models, previously characterized by Joana Paredes (at i3S) and Florence Janody (at IGC), these researchers will focus specifically on deciphering the role of P-cadherin/F-actin crosstalk in breast CSC appearance and maintenance, extending their already established collaboration.

 

Working Package 5

Centrosome amplification: is this alteration related with the gain of stem-like features by cancer cells?

(Monica Bettencourt-Dias, IGC; Sérgia Velho, Ipatimup/i3S)

Taking in account the scientific know-how of Monica Bettencourt-Dias (from IGC) in centrosomes biology, as well as the expertise of Sérgia Velho (from i3S) on the effect of myofibroblasts in colon carcinogenesis, WP5 will resolve the influence of increased centrosomes number in cancer cells in the formation of a CSC niche, which has never been addressed. An aberrant amount of centrosomes is frequently found in cancer, being significantly associated with poor patient prognosis. Thus, the WP5 team will study if an elevated number of centrosomes promotes the acquisition of CSC properties within a tumour, as well as induces transdifferentiation of fibroblasts into myofibroblasts in the tumour microenvironment, using breast and colon as models. In addition, the effect of the transdifferentiated myofibroblasts in the acquisition of CSC properties by cancer cells will also be addressed, in order to evaluate if the crosstalk between tumour and microenvironment is crucial to maintain a CSC niche.

 

Working Package 6

CSC niche: the role of cellular and non-cellular components from the tumour microenvironment

(Maria José Oliveira, INEB/i3S; Sérgia Velho, Ipatimup/i3S)

In WP6, joint efforts have been established between two principal investigators from i3S, namely Sérgia Velho (previously from Ipatimup) and Maria J. Oliveira (formerly from INEB), both aiming to further identify the molecular mechanisms by which CSC modulate and are modulated by cellular and non-cellular microenvironmental factors present at their niche, including components from the extracellular matrix (ECM), macrophages, lymphocytes, dendritic and mesenchymal stem cells (MSC). Unravelling the cellular and non-cellular intermediates, as well as the molecular factors governing CSC niche formation and maintenance may unveil new therapeutic tools to improve patient survival.

 

Working Package 7

Circulating CSCs: how to survive metabolic alterations caused by matrix detachment

(Joana Paredes, Ipatimup/i3S; Paulo Oliveira, CNC/UC-Biotech)

For WP7, a collaboration has been established between Joana Paredes’ team (from i3S) and those from Paulo J. Oliveira and João Ramalho-Santos (at CNC.IBILI), due to their expertise in breast cancer metastasis and stem cell metabolism, respectively. These teams will study how breast CSC markers are able to modulate cell metabolism, promoting an antioxidant background to CSC. Moreover, it will be evaluated if this metabolic program allows CSC to persist in extracellular matrix-detachment conditions, enhancing their resistance to cell death while in circulation.

 

Working Package 8

CSC and metastasis: relevance in brain metastatic colonization

(Joana Paredes, Ipatimup/i3S; Luís P. Almeida, CNC)

Based on preliminary data also obtained by Joana Paredes’ team (at i3S), demonstrating an enrichment of a stem-like program in brain metastatic breast cancer cells, WP8 has been proposed in collaboration with Luís P. Almeida (at CNC.IBILI), who has an increased experience in developing therapies against brain disorders, as well as the scientific and technical know-how to study brain-blood barrier (BBB) integrity. Thus, WP8 team will explore the impact of the breast CSC phenotype in BBB reliability and on brain colonization. Further, the expression of breast CSC makers will be validated in human brain metastases already available.

 

Working Package 9

Targeting CSC-associated drug resistance with nanotechnology-based strategies

(João Nuno Moreira, CNC; Maria Conceição Lima, CNC; Lino Ferreira; CNC/UC-Biotech; Helena Vasconcelos, Ipatimup/i3S)

 

In order to tackle drug resistance of CSC and design novel therapies to eliminate CSC populations, WP9 has been devised. The principal investigators João N. Moreira, Conceição P. Lima and Lino Ferreira (at CNC.IBILI) will join efforts with Helena Vasconcelos (at i3S) to assess the impact of different therapeutic strategies already in place in their labs to modulate CSC signalling-associated drug resistance and cell viability.

  
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