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Extracellular Vesicles as biomarkers of hepatic metastasis in pancreatic cancer patients
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Orientador(es)
Resumo(s)
Pancreatic cancer (PC) is currently considered a public health burden. Despite not
being one of the main types of cancer nor one of the main causes of cancer-related deaths
worldwide, the case-fatality rate extremely high.
The diagnose of metastatic disease is usually performed by imagiological exams.
However, these lack the sensitivity and specificity to detect earlier stages of the metastatic
process, such as the pre metastatic niche (PMN) and micrometastasis. Interestingly,
extracellular vesicles (EVs) have been described to be involved in the formation of the PMN
by transporting molecules from their secreting cells (both tumor and tumor-associated) to
biofluids, and thus represent an accessible source of biomarkers for disease diagnosis and
monitoring, and as prognostic and predictive tools. Hence, the main purpose of this Master
Thesis is to evaluate whether circulating EVs can early detect the presence of hepatic
metastatic disease in PC patients.
For this purpose, we have developed an animal model with PC liver metastasis, to
collect plasma and both tumor and stromal cells from the liver. Cells were cultured and
derived EVs were isolated. The detailed characterization of EVs protein composition was
performed by mass spectrometry. The results showed several proteins to be upregulated
in the plasma EVs of metastatic PC mice, as well as in the tumor or stroma derived EVs,
when compared to the plasma and stroma derived EVs of healthy mice, highlighting the
potential of EVs present in the plasma to be used as PC biomarkers. Hence, further
statistical analysis and literature reviewing were performed to select a tumor (Rab11b)
and a stromal (SERT) marker. Although both have been described to be directly or
indirectly involved in biological processes related with tumor progression, some other
studies have associated their mRNA levels with a good prognosis. Hence, we decided to
pursue with both these proteins to investigate whether their expression levels in human
plasma derived EVs could be associated with hepatic metastasis.
Our results showed that, in human plasma samples, a higher percentage of EVs
Rab11b+ was linked to longer metastasis-free survival, contrasting the findings in our PC
mouse model. Furthermore, EVs SERT+ levels showed varied associations with survival
over different timepoints, emphasizing the dynamic nature of the stromal context. A higher
tumor-stroma ratio (TSR) at 6 to 8 months post-diagnosis indicated prolonged metastasisfree
survival, highlighting the stroma's pro-tumoral role. Additional particle and
fluorescence intensity analyses yielded no major significant distinctions.
Descrição
Palavras-chave
Extracellular Vesicles biomarkers of hepatic metastasis pancreatic cancer patients