Research lines

Overview

Our group combines cell biology, proteomics, and computational approaches to understand how cell-signalling pathways driven by protein kinases contribute to the development of cancer. Expanding our knowledge of these pathways will be invaluable for advancing personalised cancer therapies. The laboratory is currently funded by an ATRAE fellowship from the Spanish Ministry of Education, Science and Universities.

Kinase substrate enrichment analysis (KSEA) from phosphoproteomics data allows quantificaiton of kinase-driven signaling pathways
Inferring signaling circuitry requires approaches that go beyond standard omics

Approach

We aim to understand how cell-signalling pathways governed by kinase activity are regulated and contribute to cancer development. We are particularly interested in the RAS-PI3K-MAPK axis as a paradigm of oncogenic signalling network that is subverted in essentially all cancer types.

While virtually all cancers deregulate one or more components of this network, the manner in which signalling is altered varies widely across individual cancer patients. As a result, targeted therapies directed at key signalling nodes often show heterogeneous patient responses. Even when patients initially benefit from these therapies, resistance frequently emerges.

To investigate the mechanisms underlying this heterogeneity, we have developed several tools to quantify kinase signalling using phosphoproteomics data, for example KSEA ( Casado et al ), and to link kinases with their substrates ( Wilkes et al, Hijazi et al ).

We are now extending these tools with methodologies that combine cell-based screening assays and mass-spectrometry-based proteomics with computational analyses. While more work is required, we believe that these approaches will allow us to measure, in a comprehensive and unbiased manner, how signalling networks are wired in individual cancer populations from functional and proteomic standpoints.

We aim to use these resources to explore the fundamental properties of signalling networks and to determine how signalling heterogeneity drives intrinsic and acquired resistance to inhibitors targeting signalling enzymes. A major focus of our work is to dissect the epigenetic mechanisms that underlie signalling heterogeneity in cancer.

Key Resources