Editorial GuideCancer

Focus Issue: From Genomic Mutations to Oncogenic Pathways

+ See all authors and affiliations

Sci. Signal.  26 Mar 2013:
Vol. 6, Issue 268, pp. eg3
DOI: 10.1126/scisignal.2004149


This two-issue series focuses on how understanding how signaling pathways are altered in cancer cells can enable researchers to develop more effective therapies. Cancer is a pleiotropic disease. Tumor cells change over time and, even within a specific tumor, cells may have different mutations and dependencies on different signaling pathways for survival or for metastatic potential. New tools and technologies for genomic- or systems-level analysis, as well as conventional biochemistry and cell biology approaches, are revealing how signaling pathways contribute to cancer development, cancer evolution, and drug resistance.

One of the most effective cancer treatments is surgery. Unfortunately, some cancers are inoperable because of their location, because they have become too widely dispersed through metastasis to secondary sites, or because they are not solid tumors. In the absence of surgery, chemotherapy and radiation therapy are the remaining options, both of which can be rather nonselective and have severe side effects. Thus, the ability to personalize therapies on the basis of the tumor’s oncogenic signaling profile may enable clinicians to devise therapies that are maximally effective and minimally toxic.

Leukemia is a cancer of the white blood cells, with some forms common in children and some common in adults. In the 26 March issue, Hartzell et al. and Casado et al. report on signaling pathways altered in two forms of leukemia, T cell acute lymphoblastic leukemia/lymphoma (T-ALL) and acute myeloid leukemia (AML), respectively. Signaling mediated by the guanosine triphosphatase (GTPase) Ras, which activates the proliferative mitogen-activated protein kinase (MAPK) pathway, is frequently aberrant in T-ALL, but relatively few patients have mutations in the Ras-encoding gene, leading Hartzell et al. to investigate what other mutations could dysregulate this pathway. By screening more than 100 pediatric T-ALL patients, they identified the Ras activator RasGRP1 as a potential contributor to this cancer. Increased RasGRP1 abundance enhanced Ras signaling and increased the proliferation of T-ALL cells, whereas reducing RasGRP1 abundance had the opposite effect. Screening patients with this cancer for increased abundance of RasGRP1 may enable customized treatment. Casado et al. focused their attention on AML cells. They combined phosphoproteomic analysis with a computational approach to boost the signal-to-noise ratio in their investigation of kinase activation patterns and the effects of select kinase inhibitors on kinase networks. Because this approach accurately predicted the relative sensitivities of patient-derived AML cells to inhibitors, such profiling of kinase networks could be applied to stratify cancers based on their predicted responses to kinase inhibition.

Kinase inhibitors, especially tyrosine kinase inhibitors, are clinically important, but many patients develop resistance to these drugs and relapse. Thus, combination therapies are needed to prevent or overcome such resistance. In the 26 March issue, Bean et al. (see the Perspective by Roulston et al.) explore the relationship between signaling of receptor tyrosine kinases and cell death (apoptosis) pathways in cancer cells “addicted” to specific receptor tyrosine kinases for survival. Their analysis of non–small cell lung cancers and a specific type of breast cancer suggests that combining drugs that inhibit antiapoptotic proteins with oncogenic kinase inhibitors may overcome drug resistance in cancer patients.

Clearly, kinase inhibitors are not the only options for rational, personalized therapeutic intervention. Protein interactions may also be important targets. The work of Bean et al. indicates that mimicking protein interactions, such as the proapoptotic effects mediated by BIM and PUMA, may be an effective strategy. Cance et al. suggest in their Perspective that interfering with the scaffolding function, rather than the kinase activity, of focal adhesion kinase (FAK), may be an effective strategy for mediating cancer-specific functional inhibition. Targeting the altered metabolism of cancer cells is another strategy that can be combined with pharmacological approaches, potentially for synergistic benefit, as described in the Perspective by Gui et al. in the Archives.

Understanding the evolution of cancers and how a tumor progresses from the noninvasive stage to the highly lethal, invasive, metastatic stage may enable clinicians to prevent this transition and thus reduce the morbidity associated with cancer. The Perspective by Webster and Weeraratna in the 26 March issue highlights research by Grossmann et al., who investigated signaling events that contributed to the invasiveness of melanoma, a particularly lethal form of skin cancer. Many tumors metastasize to the lung. Citterio et al. in the Archives focused on the signaling mechanisms that enable the metastasis of breast cancers to the lung, and Chen et al. showed that pharmacological inhibition of phospholipase D1 (PLD1) attenuates not only primary tumor growth, but also lung metastasis. Tumor heterogeneity emerged as a theme in the study by Grossmann et al. and also in research on melanoma by Biechele et al. and Jeong et al. (see the Perspective by Guardavaccaro and Clevers) in the Archives.

Identifying different subpopulations of cancer cells may yield signatures of both invasive cells and cells that might be resistant or sensitive to specific therapies. Wood et al. developed a screening and imaging analysis method to perform high-throughput screening and applied their method to identify proteins that influenced the sensitivity of melanoma cells to various clinically used antineoplastic agents. Understanding cancer heterogeneity at the genomic level is becoming possible with large-scale tumor sequencing efforts. As Yaffe highlights in a Perspective in the 2 April issue, the challenge now is to integrate this information with other systems-level studies, such as gene expression data, proteomic and posttranslational modification data, and analysis of the dynamics of signaling and metabolic networks. The Protocol by Gao et al. in the 2 April issue provides a step-by-step guide to cBioPortal, an online resource for interactively exploring genetic alterations across tumor samples, as well as changes in messenger RNA (mRNA) and microRNA expression, DNA methylation, protein abundance, and phosphoprotein abundance. These tools and the research highlighted here suggest that understanding the molecular mechanisms underlying cancer is an attainable goal and present hope for effectively combating this dreaded disease.

Featured in This Two-Issue Series

Research Articles

  • G. R. Bean, Y. T. Ganesan, Y. Dong, S. Takeda, H. Liu, P. M. Chan, Y. Huang, L. A. Chodosh, G. P. Zambetti, J. J.-D. Hsieh, E. H.-Y. Cheng, PUMA and BIM are required for oncogene inactivation–induced apoptosis. Sci. Signal. 6, ra20 (2013). [Abstract] [Full Text] [PDF]

  • C. Hartzell, O. Ksionda, E. Lemmens, K. Coakley, M. Yang, M. Dail, R. C. Harvey, C. Govern, J. Bakker, T. L. Lenstra, K. Ammon, A. Boeter, S. S. Winter, M. Loh, K. Shannon, A. K. Chakraborty, M. Wabl, J. P. Roose, Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis. Sci. Signal. 6, ra21 (2013). [Abstract] [Full Text] [PDF]

Research Resource

  • P. Casado, J.-C. Rodriguez-Prados, S. C. Cosulich, S. Guichard, B. Vanhaesebroeck, S. Joel, P. R. Cutillas, Kinase-substrate enrichment analysis provides insights into the heterogeneity of signaling pathway activation in leukemia cells. Sci. Signal. 6, rs6 (2013). [Abstract] [Full Text] [PDF]


  • W. G. Cance, E. Kurenova, T. Marlowe, V. Golubovskaya, Disrupting the scaffold to improve focal adhesion kinase–targeted cancer therapeutics. Sci. Signal. 6, pe10 (2013). [Abstract] [Full Text] [PDF]

  • A. Roulston, W. J. Muller, G. C. Shore, BIM, PUMA, and the Achilles’ heel of oncogene addiction. Sci. Signal. 6, pe12 (2013). [Abstract] [Full Text] [PDF]

  • M. R. Webster, A. T. Weeraratna, A Wnt-er migration: The confusing role of β-catenin in melanoma metastasis. Sci. Signal. 6, pe11 (2013). [Abstract] [Full Text] [PDF]

  • M. B. Yaffe, The scientific drunk and the lamppost: Massive sequencing efforts in cancer discovery and treatment. Sci. Signal. 6, pe13 (2013). [Abstract]


  • J. Gao, B. A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S. O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). [Abstract]

Related Resources

Editorial Guide

  • E. M. Adler, N. R. Gough, Focus Issue: Rendering resistance futile. Sci. Signal. 4, eg3 (2011). [Abstract] [Full Text] [PDF]

Research Articles

  • T. L. Biechele, R. M. Kulikauskas, R. A. Toroni, O. M. Lucero, R. D. Swift, R. G. James, N. C. Robin, D. W. Dawson, R. T. Moon, A. J. Chien, Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Sci. Signal. 5, ra3 (2012). [Abstract] [Full Text] [PDF]

  • Q. Chen, T. Hongu, T. Sato, Y. Zhang, W. Ali, J.-A. Cavallo, A. van der Velden, H. Tian, G. Di Paolo, B. Nieswandt, Y. Kanaho, M. A. Frohman, Key roles for the lipid signaling enzyme phospholipase D1 in the tumor microenvironment during tumor angiogenesis and metastasis. Sci. Signal. 5, ra79 (2012). [Abstract] [Full Text] [PDF]

  • C. Citterio, M. Menacho-Márquez, R. García-Escudero, R. M. Larive, O. Barreiro, F. Sánchez-Madrid, J. M. Paramio, X. R. Bustelo, The Rho exchange factors Vav2 and Vav3 control a lung metastasis–specific transcriptional program in breast cancer cells. Sci. Signal. 5, ra71 (2012). [Abstract] [Full Text] [PDF]

  • H. Grossmann, J. H. Yoo, J. Clancy, L. K. Sorensen, A. Sedgwick, Z. Tong, K. Ostanin, A. Rogers, K. F. Grossmann, S. R. Tripp, K. R. Thomas, C. D’Souza-Schorey, S. J. Odelberg, D. Y. Li, The small GTPase ARF6 stimulates β-catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis. Sci. Signal. 6, ra14 (2013). [Abstract] [Full Text] [PDF]

  • W.-J. Jeong, J. Yoon, J.-C. Park, S.-H. Lee, S.-H. Lee, S. Kaduwal, H. Kim, J.-B. Yoon, K.-Y. Choi, Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis. Sci. Signal. 5, ra30 (2012). [Abstract] [Full Text] [PDF]

Research Resource

  • K. C. Wood, D. J. Konieczkowski, C. M. Johannessen, J. S. Boehm, P. Tamayo, O. B. Botvinnik, J. P. Mesirov, W. C. Hahn, D. E. Root, L. A. Garraway, D. M. Sabatini, MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma. Sci. Signal. 5, rs4 (2012). [Abstract] [Full Text] [PDF]


  • D. Guardavaccaro, H. Clevers, Wnt/β-catenin and MAPK signaling: Allies and enemies in different battlefields. Sci. Signal. 5, pe15 (2012). [Abstract] [Full Text] [PDF]

  • D. Y. Gui, C. A. Lewis, M. G. Vander Heiden, Allosteric regulation of PKM2 allows cellular adaptation to different physiological states.Sci. Signal. 6, pe7 (2013). [Abstract] [Full Text] [PDF]

View Abstract

Related Content

Navigate This Article