ITQB: ACM - PhD Thesis
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- Assessing tumour-associated macrophage phenotype and glycan signatures in breast cancer: Insights from 3D cell models and protein microarraysPublication . Lopes, Nuno; Brito, Catarina; Palma, Ângela"Breast cancer (BC) remains the cancer type with highest incidence in women, being the leading cause of cancer-related mortality. Among all subtypes, triple negative BC (TNBC) presents the worst prognosis, with the highest rates for recurrence and progression. Despite the dire scenario for TNBC, scarce therapeutic options are available, relying primarily on chemotherapy. In past years, the immune microenvironment has been recognised as an attractive strategy to target TNBC. High infiltrates of tumour-associated macrophages (TAMs), particularly, have been reported in TNBC, mediating immunosuppressive events.(...)"
- Immunocompetent 3D human CNS Models: a novel approach for preclinical development of gene therapiesPublication . Gomes, Catarina"Recombinant adeno-associated virus (rAAV) gene therapies hold significant promise for treating central nervous system (CNS) disorders. However, their effectiveness in clinical settings is often limited by the immune responses mounted by the host. Astrocytes and microglia, the resident immune cells of the CNS, play a crucial role in initiating innate immune responses, which can lead to neuroinflammation. However, a comprehensive understanding of the molecular mechanisms driving and sustaining glial cell activation remains unclear due to the lack of human models illustrating the neuro-immune axis. To accelerate the clinical use of rAAVs, thorough preclinical evaluation of their efficacy and safety in human models is essential. The in vitro replication of CNS phenotypic and functional characteristics requires advanced culture techniques to closely emulate the structural and molecular complexity of in vivo systems. Models derived from the differentiation of human induced pluripotent stem cells (hiPSCs) in a three-dimensional (3D) environment hold potential as complementary tools for animal-based preclinical research. This thesis aims to create innovative human 3D CNS models that effectively replicate the key features of neuroinflammation by integrating hiPSC technology with stirred-tank bioreactor systems and utilizing a broad array of characterization methods. The models developed for advancing preclinical research of ATMPs, specifically viral-based gene therapies, demonstrated significant potential.(...)"
- The effect of dual HER2 blockade on anti-tumor immune cellsPublication . Batalha, Sofia; Brito, Catarina"Breast cancer (BC) remains the deadliest female malignancy. The surrogate subtypes displaying (over)expression of the HER2 receptor (HER2+ ) display some of the worse prognosis and survival rates. The incorporation of antiHER2 biologicals in the clinics has dramatically improved HER2+ BC prognosis. However, most patients treated with the anti-HER2 antibody trastuzumab eventually relapse due to therapy resistance. The development of alternative anti-HER2 therapies, namely the combined use of two HER2-blocking antibodies (trastuzumab and pertuzumab), brought clinical improvement....)"
- The impact of the genetic risk factor BIN1 to Alzheimer’s disease developmentPublication . Perdigão, Catarina" Alzheimer’s disease (AD) was identified more than a century ago. Yet, there is still no cure and the mechanisms behind the most common form of AD (late-onset, LOAD) are still an open question. BIN1 was the second gene most frequently associated with LOAD. Bin1 depletion has been linked with AD earliest pathomechanisms: increased beta-amyloid (Aβ) accumulation, endosomal abnormalities, and synaptic defects. Sequencing of BIN1 genomic locus identified regulatory and coding variants of BIN1, indicating that Bin1 correct levels and function are essential for a healthy brain. Two coding variants associated with LOAD (rs754834233, Bin1-PL, and rs138047593, Bin1-KR) lead to missense mutations in Bin1 protein. This work aimed to understand whether LOAD mutations in BIN1 result in Bin1 loss of function and contribute to LOAD early mechanisms. "
- Tumor microenvironment models: ex vivo, in vitro and in silico approaches to address targeted therapiesPublication . Cartaxo, Ana L"Cancer is the second leading cause of mortality worldwide, despite the extraordinary advances in the last two decades due to the development of targeted therapies. These target particular molecules required for cell growth and tumorigenesis; nonetheless, de novo or acquired resistance to therapy often lead to patient relapse and disease progression. There is cumulating evidence supporting the importance of tumor microenvironment (TME)-driven mechanisms in cancer progression and drug resistance. Therefore, there is a need for cancer models in which critical components of the TME, such as the non-malignant cell types and the extracellular matrix (ECM), are represented and tissue architecture is maintained. (...)"
- Neural cell models for disease modeling and drug discoveryPublication . Terrasso, Ana Paula Barreto"Neurological disorders are a major public health problem and are expected to rise dramatically together with the higher life expectancy and the shift towards an ageing society. Current therapeutic options can only ameliorate some of the symptoms and there are no effective treatments to target pathological mechanisms and stop disease progression. The human brain complexity hampers the understanding of the brain functioning at the molecular, cellular, and pathophysiological levels for many neurological disorders. This highlights the need for new brain models, which can contribute to unveil molecular mechanisms of neurological disorders, identify therapeutic targets and evaluate preclinically new therapies in a more adequate and predictive basis, withstanding its successful translation to the clinics. Despite their undeniable value, traditional animal models diverge from humans at biochemical and genetic levels. Moreover, 2D in vitro cell-based models do not mimic important aspects of brain cellular heterogeneity, architecture and microenvironment (...)".