Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body, forming a Malignan tumor
https://www.who.int/news-room/fact-sheets/detail/cancer
https://www.wikiwand.com/en/Cancer
By overall global mortality
Phosphoproteomics. Protein Phosphorylation the quantification of phosphorylation offers the opportunity to quantify cell signalling comprehensively and without bias. However, the large number of phosphorylation sites means large number of samples are needed to obtain good statistically significant results.
genes with roles in regulating intracellular signalling pathways are frequently mutated or otherwise dysregulated in tumour cells. On the other hand, tumour cells secrete factors that corrupt ‘normal’ untransformed cells in their vicinity.
Creixell, P., Schoof, E. M., Simpson, C. D., et al. (2015). Kinome-wide decoding of network-attacking mutations rewiring cancer signaling. Cell, 163, 202–17.
Drake, J. M., Paull, E. O., Graham, N. A., et al. (2016). Phosphoproteome integration reveals patient-specific networks in prostate cancer. Cell, 166, 1041–54.
In tumours, cell-to-cell communication allows cancer cells to recruit Stromal cells to their vicinity which in turn provide an environment where cancer cells can proliferate and ultimately invade adjacent and distant tissue. This form of heterotypic communication is mediated by secreted factors, which may be soluble or embedded in vesicles, and by direct cell-to-cell contacts. Proteomics approaches are being fun- damental to our understanding of the protein composition of the tumour microenvironment, including those present in the soluble form (i.e. the secretome) and those that are present in vesicles (exosomes). Proteomic approaches are also contributing to the understanding of how cells to communicate by direct contact with each other.
Cancer Secretome
The protein composition of cancer secretomes has been exten- sively investigated in order to identify biomarkers of disease (Gronborg et al., 2006; Pavlou and Diamandis, 2010).
secreted pro- teins, which include interleukins, VEGF, CCL2 and CCL20, in- duce inflammation and impact senescence in vivo (Acosta et al., 2013).
KSEA identified the kinases mTORC1 and MAPK2K2 as being involved in the regulation of the oncogene- induced secretome (Herranz et al., 2015) thus providing a poten- tial rationale for the observed beneficial effects of mTOR inhibitors in preventing ageing and cancer (Zhuo et al., 2009; Hasty, 2010).
Cancer Exosome
Welton et al. Bladder cancer secreted exosomes with antigens involved in immune modulation.
Heterotypic signalling (between different types of cells; cancer communicating with nearby cells mostly, paracrine signaling)
good technique: cell type-specific labelling using amino acid precursors (CTAP). See more at Cell signaling.
Crass in pancreas cancer. Tape et al.
Tape, C. J., Ling, S., Dimitriadi, M., et al. (2016). Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell, 165, 910–20.
Cancer-triggering mutations
essentially all cancers deregulate genes with roles in regulating intracellular signalling. See cancer dependency map from Achilles project.
There are many parallel pathways and adaptation mechanisms, so that blocking one may not reduce its effect, as there may be parallel causes, or compensating mechanisms. Several of these have been found for melanoma and others by looking at phosphoproteomics, for e.g.
Given the existence of a multitude of mechanism by which kinase signalling pathways may be aberrantly activated in cancer, inferring kinase pathway activation using proxies such as genetic mutations or protein expression is likely to result in erroneous conclusions. This is most relevant for treatment, maybe less for diagnosis (where correlations are fine, while in treatment causation is crucial)?
Inferring signaling pathways from phosphorylation measurements. Ochoa et al. used KSEA to compile an atlas of kinase activation across dif- ferent tissues and to identify new hypotheses on kinase regulation (Ochoa et al., 2016)
Oncogenes
deactivation of Tumour suppressors
Mertins, P., Mani, D. R., Ruggles, K. V., et al. (2016). Proteogenomics connects somatic mutations to signalling in breast cancer. Nature, 534, 55–62.
The reliance on anaerobic glycolytic metabolism as a source of energy and enhanced lactate production relative to untransformed cells are well understood traits of cancer cells (Warburg effect)
Patti, G. J., Yanes, O., & Siuzdak, G. (2012). Innovation: metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol, 13(4), 263–9.
Oncometabolites
Looking for cancer-specific Antigens (mostly surface molecules, like Major histocompatibility complex (MHC))
Khodadoust, M. S., Olsson, N., Wagar, L. E., et al. (2017). Antigen presentation profiling reveals recognition of lymphoma immuno- globulin neoantigens. Nature, 543, 723–7.
Park et al. (2010) found that Hypoxia promote the secretion of proteins and exosomes with potential roles in angiogenesis and metastasis
a phosphoproteomic study of integrin signalling identified several potential kinases involved in metastasis, of which integrin-regulated kinases, DBF4, PAK2, and GRK6, were validated by siRNA to have a role in cell adhesion and migration possibly through their regulation of actin cytoskeleton dynamics (Chen et al., 2009).
Sciacovelli, M., Goncalves, E., Johnson, T. I., et al. (2016). Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transi- tion. Nature, 537, 544–7.
The challenge now is to develop computational approaches capable of integrating the large volumes of data obtained with state-of-the- art mass spectrometry and with those from other -omic data sets, such as those obtained by whole genome sequence and RNAseq gene expression analyses. E.g. proteogenomics!