Metabolism and Cell Signaling

Overview

The Group of Metabolism and Cell Signaling studies the crosstalk between cellular metabolic and bioenergetic flows with signaling processes, and how this interaction contributes to coordinate the growth and homeostasis of cells and tissues. In particular, we study how these interaction mechanisms are deregulated in cancer at the molecular and cellular level. During last years, the group has established the processes of interaction between the metabolism of the amino acid glutamine, the most abundant in human blood and the most important from an energetic point of view for cells, with cell signaling via the mTOR pathway, a protein complex essential in the regulation of cell growth and metabolism, and autophagy. In addition, we are also interested in the identification of the extralysosomal targets of the lysosomal proteases shown to be involved in the regulation of a plethora of physiological processes, such as mitosis, gene expression, or differentiation.

Research Highlights

Glutamine, mTOR and autophagy: a multiconnection relationship

Cancer cells metabolize glutamine mostly through glutaminolysis, a metabolic pathway that activates mTORC1. The AMPK-mTORC1 signaling axis is a key regulator of cell growth and proliferation. Our recent investigation identified that the connection between glutamine and AMPK is not restricted to glutaminolysis. Rather, we demonstrated the crucial role of ASNS (asparagine synthetase) and the GABA shunt for the metabolic control of the AMPK-mTORC1 axis during glutamine sufficiency. Our results elucidated a metabolic network by which glutamine metabolism regulates the mTORC1-macroautophagy/autophagy pathway through two independent branches involving glutaminolysis and ASNS-GABA shunt.

FGFR1 inhibition improves therapy efficacy and prevents metabolic adaptation associated with temozolomide resistance in glioblastoma

Recurrent therapy resistance is a major limitation in clinical efficacy and for the outcome of glioblastoma (GBM) patients, positioning GBM among the tumor types with the poorest survival outcomes. In this work, we dissected resistance mechanisms in GBM, which resulted in the identification of FGFR1 pathway as a major regulator of the signaling and metabolic rewiring associated with temozolomide (TMZ) resistance in GBM. Hence, we described a mechanism of resistance that operates at two major levels. First, a p53-mediated regulation of cell cycle inducing cell cycle arrest to allow DNA repair in response to TMZ. And second, a complete metabolic rewiring promoting lipid catabolism and preventing lipid peroxidation. Both the p53-mediated response and the metabolic adaptation are controlled by FGFR1, as inhibition of the FGFR1 pathway completely abolishes this signaling and metabolic reprograming, restoring sensitivity to TMZ. Our results also indicated a correlation of FGFR1 levels with poor prognosis in GBM patients, and validated the treatment of TMZ in combination with FGFR1 inhibitors as an efficient strategy to induce tumor cell death in pre-clinical animal models. This data position the receptor FGFR1 as a very promising candidate for evaluation in future clinical approaches to limit the development of therapy resistance to TMZ in GBM patients (Figure 1).

Asparagine endopeptidase contributes to genotoxic stress resistance through ATR regulation in invasive ductal breast carcinoma

This project is led independently by Jonathan Martínez-Fábregas. Lysosomal proteases have frequently been implicated in the initiation and progression of cancer, but the underlying mechanisms remain poorly understood limiting the capacity to design new strategies for cancer treatment. We demonstrated that the lysosomal protease asparagine endopeptidase (AEP) accumulates in the nuclei of breast cancer cells, thereby contributing to their resistance to genotoxic stress. We demonstrated that AEP deficiency in cancer cells leads to increased sensitivity to genotoxic insults, resulting in genomic instability and cell death. Our findings also revealed that AEP specific inhibition sensitizes breast cancer cells to chemotherapy drugs cisplatin and etoposide. Interestingly, a negative correlation between AEP and ATR protein levels in breast cancer patients using data available from the TCGA database, have been found. Thus, those patients expressing high levels of AEP show low levels of ATR and poorest outcome and response to radiation therapy. Finally, all these data have been further corroborated by immunofluorescence using an independent cohort of human invasive ductal breast carcinoma samples, confirming that non-responder patients exhibited high levels of nuclear AEP leading to reduced ATR levels, in comparison to responder patients. Our data provide novel strategies for treating resistant tumors by combining AEP inhibitors with current chemo- and radiotherapy approaches, to enhance sensitivity to genotoxic insults. In other context, we are also interested in unravelling the role of chronic inflammation and the IL6/CtsL axis in the regulation of liver-related diseases and hepatocellular carcinoma (Figure 2).