For a description of our work on cancer in plain English, see the home page.
Our long-term goal is to understand how networks of biochemical reactions cooperate to the maintenance of cellular functional states and cellular homeostasis. More specifically, we are studying how biochemical networks encode for cellular decisions underlying cell and tissue homeostasis and how oncogenes contributes to early tumour initiation and promotion by reprogramming these processes. We focus our studies on the characterization of checkpoint signalling and the DNA damage response (DDR) with particular interest on their heterogeneous response among clonal population of cells and how oncogenes alter their functioning. We have raised biochemical tools to monitor or alter K-RAS (and its mutants), p53, Caspases and DDR-related kinases.
KRAS signaling and early oncogenesis
The leading causes of non-gender specific cancer-related mortality are lung, bowel and pancreatic cancers, tumours often driven by mutations in K-RAS (19%, 45% and 98% of the total cases, respectively). Despite the colossal efforts to understand RAS biology and its implication in cancer and the vast knowledge we have acquired about RAS in the last decades, this knowledge seems to have not translated into advances in therapeutic intervention as yet. This is particularly evident in pancreatic cancer, where almost the entirety of cancers presents a K-RAS mutation at the G12 residue, exhibits very poor prognosis with survival rates that have not improved over the last decades. Several obstacles to effective therapy have been identified, for instance thoroughly reviewed by Cox et al.: the difficultly to directly drug RAS, the complexity of RAS effector signalling network, the existence of different RAS isoforms and different – functionally diverse – oncogenic mutations, cooperation with mutations in other genes and interference with the wild-type K-RAS allele. Our approach, targeted to the understanding of networks in living cells, is of strategic value in resolving some of these obstacles.
We have undertaken a systematic analysis of how genetic mutations alter the dynamic topology of K-RAS effector signalling networks leading to diverse cancer-associated phenotypes. We are also characterizing the large non-genetic heterogeneity observed at the signgaling and phenotypic level. We focus on the understanding of how KRAS mutations rewire signaling pathways during early oncogenesis, hoping to discover novel mechanisms that can be levaraged for therapeutic or diagnostic purposes.
The DNA damage checkpoint
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Single-cell biochemistry and the DNA damage response
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