Cancer Drug Resistance

ABOUT

Some tumour cells including the cancer stem cells are multidrug resistant (MDR). Our overall objectives are to:

i) Identify and validate novel molecular targets to overcome MDR in cancer;

ii) Identify novel therapeutic approaches to target MDR tumour cells, particularly the cancer stem cells;

iii) Identify novel means to diagnose MDR and minimal residual disease in haematological tumours.

 

RESEARCH

i) Regarding the identification of novel molecular targets to overcome MDR, we have been focusing on molecular mechanisms related to the MDR phenotype, particularly those related to the metabolic alterations of MDR cells and to the intercellular communication mediated by extracellular vesicles (exosomes and microvesicles) shed by MDR cells. We identified metabolic alterations in MDR cells, which may be transferred to drug-sensitive cells by extracellular vesicles (exosomes and microvesicles) released by the MDR cells (Scientific Reports, 2017). This work was possible due to collaborations with the NICB (Dublin City University, Ireland), with CIC bioGUNE (Spain) and with the University of Belgrade (Serbia).

ii) Regarding the study of novel therapeutic approaches to target MDR tumour cells, we have been studying novel potent small molecule inhibitors of the MDR phenotype (collaborations with CIIMAR, FFUP, UCIBIO/REQUIMTE) and nanotechnology-based strategies aiming to target particularly the cancer stem cells or tumour initiating cells (collaboration with CNC). More recently we have initiated a collaboration with the MIT (USA), aiming to study metakaryotic stem cells.

iii) Regarding the identification of means to diagnose a MDR phenotype in order to support clinical decisions, we are identifying tumour biomarkers on circulating tumour extracellular vesicles and on microRNAs obtained from liquid biopsies of patients with haematological cancers (acute myeloid leukaemia or multiple myeloma). This work is possible due to a strong collaboration with Centro Hospitalar São João (CHSJ).

The intercellular transfer of Pgp from drug resistant to drug sensitive cells may be mediated by extracellular vesicles.  This confocal microscopy image shows expression of Pgp in non-Pgp expressing drug sensitive cells following co-culture with extracellular vesicles from drug resistant (Pgp-overexpressing) cells. Nuclei are labelled in blue (with DAPI), plasma membrane and Golgi are stained in red (with WGA) and Pgp is detected in green (with FITC).