Cancer, generally speaking, occurs due to unregulated cell reproduction. As cells grow and multiply unchecked they need to produce more proteins, ultimately leading to the formation of tumors. While it has long been known that cancer cells increase their production of proteins, the interface between production of proteins and gene expression in cells has remained unclear. In a 2013 study published in the journal Science, a research team used complex analyses to better understand these interactions. Through the use of Common Fund supported LINCS data, the researchers were able to show that HSF1, a critical cell regulator, was highly controlled by the production of proteins. The LINCS data used for these analyses are a large catalog of how human cells react at the genetic level to changes induced by a vast array of chemicals or interfering genetic molecules. The analyses of the data showed that the response of cells to an agent that blocks proteins from being made is similar to their response when a protein that controls genes is blocked, suggesting that this protein (HSF1) regulates the production of proteins in the cells. This is a key finding in better understanding why cancer cells continue to have energy, while ordinary cells would otherwise be worn out. HSF1 has long been known to be a critical regulator in cancer, playing a large role in maintaining uncontrolled growth. Therefore understanding how HSF1 is controlled is an important finding in the search for improved cancer treatments. In the study, the research team was able to use this information to reverse HSF1 activation and suppress tumor growth in a mouse model. In the model, human leukemia cells were grafted into the mice, showing that the effects have a potentially promising role in humans. These results are very encouraging for future studies that could impact a number of tumor-forming cancers affecting humans.
Santagata S, Mendillo ML, Tang YC, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr, Whitesell L, Lindquist S. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science, July 19, 2013; 341. PMID: 23869022.
More effective therapeutics are needed for numerous conditions affecting people, yet drug development remains inefficient. Investigators supported by the Common Fund Library of Integrated Network-based Cellular Signatures (LINCS) program have discovered new insights into the pharmacological properties of drugs that should help us design better therapeutics and more accurately predict their effects. While most studies of drug effects focus on measures of drug potency, e.g., by emphasizing the dose needed to experimentally reduce cell numbers in half, Fallahi-Sichani and colleagues at Harvard Medical School and the Oregon Health and Science University found that other measures of the response of cells to drugs can provide additional insights. They found that different measures are more informative at different doses of the drug response, e.g., some are more informative at higher doses and some at lower doses. They also found that the different measures do not always correlate with each other, e.g., when compared across different drugs or different cell types. Yet some measures correlate with cell type and others with drug class. In addition, the different measures each reveal unique information that contributes insights into the action of the drug. The findings indicate that it is worthwhile to compare multiple parameters when examining the variability of drug effects, and expand the way we should think about parameters of drug activity. In some cases the underlying explanation comes from how individual cells might behave differently from a population of cells.
Fallahi-Sichani M, Honarnejad S, Heiser LM, Gray JW, Sorger PK. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol. 2013 Sep 8. PMID 24013279.
The Common Fund is supporting two awards totaling $12.7 million dollars in the Library of Integrated Network-Based Cellular Signatures (LINCS) program. The awards support the high-throughput collection and integrative computational analysis of molecular activity and cellular signatures generated in response to a variety of perturbing agents in a multiple cell types. The new knowledge generated by this program will serve as a long-term resource for the scientific community.
- One new award, given to Drs. Todd Golub and Wendy Winckler of the Broad Institute, supports the application of a novel approach to analysis of genome-wide expression to catalogue the cellular consequences of 4,000 diverse small molecules and genetic perturbations in an array of twenty different human cell types representing biological diversity and interest in the broad scientific community. The work will establish the information resource needed to support the discovery of unknown components of the genome, annotate the function of small molecules, and link disease states with small-molecule or signatures of genetic perturbation to provide insight into the biological basis of disease and potential new therapeutics (1U54-HG006093-01)
- The second award given to Drs. Timothy Mitchinson and Peter Sorger of Harvard University, supports the development of a new research center to advance the knowledge of disease processes, drug mechanisms and selectivity, and ultimately patient-specific responses to therapy. The center will focus on small molecule kinase inhibitors as versatile perturbagens which may be targeted in new therapies. The researchers will characterize the response to these perturbagens in 45 different cell lines known for diverse drug responses and for which genomic data are available, and then in more than 1000 human tumor cell lines (1U54-HG006097-01)
Biomedical research data generated from genomics analyses, imaging, biochemistry and other assays are abundant yet difficult to integrate using conventional approaches and databases. To address this need, Dr. Peter Sorger and colleagues at Harvard Medical School, Massachusetts Institute of Technology, and the University of Applied Sciences in Germany, researchers supported through the Common Fund’s Library of Integrated Network Based Cellular Signatures (LINCS) program, have developed an innovative new adaptable method that allows different types of complex data sets to be stored, analyzed and extended. In a recent paper in Nature Methods, they demonstrate the utility of the approach, which exploits useful aspects of two data file formats (HDF5 and XML), for analyzing a complex imaging data set reflecting 160 experimental conditions in over a million different single cells. The approach led to the discovery of new pharmacological relationships between compounds that bind and inhibit epidermal growth factor receptors (EGFR), providing insights into cell-to-cell variability in response to drugs.
Millard BL, Niepel M, Menden MP, Muhlich JL, and Sorger PK. Adaptive informatics for multifactorial and high-content biological data. Nat Methods. 2011. Vol 8(6):487-493.