Lipid metabolism alterations in colorectal cancer : potential clinical relevance in the prognosis of the disease

• Autores: Silvia Cruz Gil
• Directores de la Tesis: Ana Ramírez de Molina (dir. tes.), Ruth Sánchez Martínez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019
• Idioma: inglés
• Número de páginas: 240
• Tribunal Calificador de la Tesis: Manuel Serrano Marugán (presid.), Gemma Domínguez Muñoz (secret.), Héctor Peinado (voc.), Agustín Rodríguez González (voc.), Enrique Casado Sáenz (voc.)
• Materias:
  • Química
    • Bioquímica
      • Lípidos
  • Ciencias de la vida
    • Fisiología humana
      • Metabolismo humano
  • Ciencias médicas
    • Patología
      • Oncología
    • Farmacodinámica
      • Procesos metabólicos de los medicamentos
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Colorrectal cancer (CRC) is the third most diagnosed cancer worldwide with nearly a million of deaths yearly. CRC does not present symptoms until advanced stages, leading to a reduction of the treatment efficacy. Therefore, new biomarkers for early detection need to be assayed. Alterations in different metabolic pathways such as carbohydrates have been broadly analyzed, but new elements of the metabolism have increased its importance in malignant progression, such as lipid metabolism. We first described a metabolic acyl-CoA synthetase (ACSL)/ stearoyl-CoA desaturase (SCD) (ACSL1/ACSL4/SCD) signature leading to enhanced invasive and migratory capacities and to the stimulation of several survival pathways to CRC cells. This mesenchymal phenotype is restored to the epithelial one upon reactivation of the master metabolic regulator, AMPK. Regarding the individual contribution of the ACSLs/SCD network enzymes; ACSL4 overexpression is related to increased proliferation and migration and to a more glycolytic phenotype; while ACSL1 overexpression stimulates invasion and metastasis markers presenting a lower basal respiratory rate. ACSL1 overexpressed cells are also characterized by acylcarnitines elevation. Polyunsaturated fatty acids (PUFA) lower levels, probable due to a greater utilization, is the main feature for ACSL4 pro-proliferative cells; while monounsaturated fatty acids (MUFA) upregulation characterize the individual overexpression of SCD. However, the simultaneous overexpression of the axis enzymes ACSL/SCD implies upregulated phospholipids and urea cycle derived metabolites showing that the global effect of the network is not performed by the sum of the individual overexpression effects. ACSL/SCD network present also a better overall energetic status showed by lower basal respiration levels and upregulated creatine pathway. Other invasive CRC cell lines present these same features converting ACSL/SCD axis in an example of metabolic adaptations for a more invasive phenotype.

    Thus, the development of clinical biomarkers or new therapies targeting this metabolic network may be useful for the cancer progression blockade. In this sense, ACSL/SCD overexpression correlates with poorer clinical outcome and increased risk of relapse of stage-II colon cancer patients. Moreover, ACSL/SCD chemical inhibition by a combined specific treatment decreases cancer cell viability without affecting normal colon cells. Post-transcriptional regulation by microRNAs (miRNAs) also represents a therapeutic opportunity for ACSL/SCD axis. We described miR-544a, miR-142 and miR-19b-1 as major overall regulators of the metabolic axis. Outstandingly, miR-19b-1 is able to inhibit invasion in several CRC cell lines, and lower miR-19b-1 expression is related with poor survival rate in CRC patients (stages II and III); according to ACSLs/SCD overexpression involvement in patient relapse. This miRNA, therefore, could be used therapeutically or as a prognostic miRNA with a potential noninvasive biomarker role for disease-free survival (DFS) in CRC patients.

    CRC-like organoids represent an excellent physiological tool modeling stages I to IV of intestinal tumors. We show that ACSL4 expression augmented with the stages in the organoids while miR-19b-1 diminished its expression. Besides, since metformin is able to rescue the invasive and migratory phenotype conferred to cancer cells upon ACSL/SCD axis overexpression; we checked the effect of this treatment in organoids, resulting in a viability decrease in first tumor phases and in a downregulation of the intestinal stem cell biomarker LGR5, becoming an appealing chemotherapy drug for intestinal cancers. According to ACSL/SCD metabolic switch, metformin action in CRC organoids is not related to a Warburg-effect impairment. This research contributes to the current issue of the use of metformin as an anticancer drug in CRC, and reveals organoids as a representative tool to assay tumor stage-dependent drugs and as a model for specific and personalized treatment.