KRAS signalling and early oncogenesis
The leading causes of non-gender specific cancer-related mortality are lung, bowel and pancreatic cancers, tumours that are often driven by mutations in KRAS (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 KRAS 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 difficulty 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 KRAS 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 KRAS effector signalling networks leading to diverse cancer-associated phenotypes. Our work relies on the use of isogenic panels of KRAS mutant cells, KRAS-inducible cell lines, transcriptomics, bioinformatics and modular response analysis. We aim to discover novel mechanisms that can be leveraged for therapeutic or diagnostic purposes.
After our earlier work on cell-to-cell variability in cell decisions at the DNA damage checkpoint, we are now refocusing our work on non-genetic heterogeneity in signalling and metabolic pathways in the context of KRAS oncogenic signalling. When a cell acquires a KRAS mutation, it can trigger tumour suppressive mechanisms (e.g., cell death or senescence) or gain a fitness advantage that might, over time, lead to cancer. Also, tumours that accrued mutations in KRAS-related pathways can be treated with targeted drugs, but while a significant fraction of cells can be killed, others may escape leading to aggressive and resistant cancers. Although genetic basis for these phenomena are known, it is increasingly apparent that non-genetic factors also play a fundamental role in these processes. With the tools we have developed to establish a live single-cell systems-biology of cellular decisions, we are now characterizing the large non-genetic heterogeneity observed at the signalling, metabolic and phenotypic level. We aim to understand the role of non-genetic heterogeneity in early oncogenesis and therapeutic response and how genetic variability in KRAS-driven cancers might synergize with this process to make KRAS-driven tumours a very difficult disease to treat.
People: Mr Pablo Oriol Valls (since 2018), Ms Annie Howitt (since 2019) and Dr Andrew Trinh (since 2019). Collaborator: Dr Christian Frezza at the MRC CU.
Tumour initiation is a process of sequential genetic and biochemical alterations occurring over time in a three-dimensional environment. However, cooperation and competition of cellular populations within a living tissue are also fundamental, yet not fully understood, mechanisms underlying tumour initiation and promotion. Therefore, more accurate observations and modelling of these heterogeneous cellular populations are of strategic importance for the understanding of cancer and, consequently, to design future therapeutic interventions. It is increasingly recognised that cell-to-cell communication is fundamental in maintaining tumour heterogeneity and plasticity and to determine early steps in oncogenesis. We are carrying out theoretical work to understand how DNA mutations and cell-to-cell communication can contribute to the early stages of carcinogenesis [BIORXIV/2018/431478].
We are also grateful for the very recent funding provided by the Cancer Research charity to study this process experimentally. Within a project code-named OncoLive we are establishing biophysical and genetic techniques to enable us seeding genetic mutations in a highly controlled spatiotemporal way and to quantify in time the consequences on biochemical networks and clonal dynamics in three-dimensional cultures.
Collaborators: Dr Maria Alcolea (joint PI) at the Stem Cell Institute in Cambridge and Dr Philip Greulich (co-I) at the University of Southampton.