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Auto-fluorescent intracellular sink - A novel Inherent biomarker for drug discovery in pancreatic cancer stem cells

  • Autores: Irene Miranda Lorenzo
  • Directores de la Tesis: Christopher Heeschen (dir. tes.)
  • Lectura: En la Universidad Autónoma de Madrid ( España ) en 2013
  • Idioma: inglés
  • Tribunal Calificador de la Tesis: Manuel Hidalgo Medina (presid.), Francisco J. Cubero (secret.), Emilio Alba Conejo (voc.), María Soledad Soengas González (voc.), Amparo Cano (voc.)
  • UNESCO :
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  • Resumen
    • Pancreatic adenocarcinoma (PDAC), the fourth leading cause of cancer-related death world-wide, is a malignant neoplasm of the exocrine pancreas. It has been hypothesized that a subset of tumour cells with stem-like properties, termed cancer stem cells (CSCs), drives pancreatic tumour growth, metastasis, and chemoresistance. While multiple surface markers such as CD133 and CD44 have been successfully used to isolate and characterize CSCs, their expression are not exclusively linked to a CSC functional phenotype. Therefore, since isolating and characterizing CSCs is of paramount importance for better understanding pancreatic cancer, we sought to identify new and novel markers that functionally enrich for CSCs using primary human pancreatic cancer cells. While classic approaches, such as cell surface expression of known CSC markers or side population were either prone to alterations by the tissue culture environment or did not enrich for CSCs, we inadvertently identified a distinct population of cells characterized by a subcellular compartment exhibiting strong autofluorescence, which did exhibit defined CSC characteristics. Specifically, these autofluorescent cells were markedly enriched both in sphere culture and during chemotherapy, strongly expressed pluripotency-associated genes, and were highly invasive both in vitro and in vivo. Most importantly, they were exclusively tumourigenic in vivo at the single cell level and were capable of recapitulating the heterogeneity of the parental tumour. Autofluorescence was determined to be due to an accumulation of riboflavin in membrane-restricted cytoplasmic structures by means of the ATP-dependent ABCG2 transporter, which did not overlap with cells defined as the side population, but could be selectively abrogated with the ABCG2 inhibitor Fumitremorgin C. In addition, we show that autofluorescence is not restricted to PDAC, as HCC, CRC or NSCLC also contain autofluorescent cells. Thus, to take advantage of this broadly detectable phenotype, we developed a low throughput drug screening platform, and show that autofluorescent CSCs are highly amenable to anti-cancer compound screening. Thus, unbiased and label-free tracking of autofluorescent cells in cancers, such as PDAC, represents a promising new technological advancement that can be used not only for isolating and studying CSCs, but can be additionally exploited for low throughput screening of compounds with anti-cancer activity in a clinical setting.

      Palabras Clave: CSC marker, Autofluorescence, PDAC,

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