New connections: Detecting tumor-specific signaling

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Sci. Signal.  11 Oct 2016:
Vol. 9, Issue 449, pp. ec233
DOI: 10.1126/scisignal.aal1624

As Chief Scientific Editor Michael Yaffe pointed out in 2013, researchers need to look beyond genomic differences in cancer, which are technically easy to identify, and develop methods to delve into the signaling differences that cause cancer’s dysregulated behavior. In this week’s issue, Simmons et al. describe a method, which they call FFPE-DISSECT, for analyzing single-cell differences in signaling pathway activity in archival fixed biopsy tissues from patients. They applied the method to colon biopsies from patients with colorectal cancer and identified distinct signaling profiles in different cells of the proliferative colon crypt and altered profiles in malignant crypt cells. Not only can this technique be applied to repositories of tissues samples to reveal cellular heterogeneity in different cancers, but can serve as a tool for disease characterization in patients to enable personalized treatment strategies. In the 12 July 2016 issue, Croucher et al. present a method that investigates a molecular level of signaling diversity that of signaling mediated by different dimers of receptor tyrosine kinases. Their method combines conformation-specific nanobodies with a protein-fragment complementation assay with affinity purification and is called bimolecular complementation affinity purification (BiCAP). Application of BiCAP to breast cancer cells revealed distinct signaling pathways that were regulated by the epidermal growth factor receptor (EGFR) family member ERBB2 when dimerized with EGFR or ERBB3. Because changes in protein partners may contribute to disease or drug resistance, this method presents an approach to investigate how to exploit signals mediated by specific protein-protein interaction networks for patient therapy. Smith et al. also investigated EGFR signaling in human cancer biopsy tissue, in this case using a proximity ligation assay (PLA) to detect when EGFR was in close proximity to its signaling adaptor GRB2. EGFR:GRB2 PLA detected increased EGFR signaling in tumors lacking mutations in the receptor, which would have been undetectable by genetic analysis, and predicted therapeutic responsiveness to EGFR inhibitors. This trio of papers illustrates the advantages to assessing not just the genetic differences in cancer cells but also the signaling differences to optimize and personalize treatment strategies.

A. J. Simmons, C. R. Scurrah, E. T. McKinley, C. A. Herring, J. M. Irish, M. K. Washington, R. J. Coffey, K. S. Lau, Impaired coordination between signaling pathways is revealed in human colorectal cancer using single-cell mass cytometry of archival tissue blocks. Sci. Signal. 9, rs11 (2016). [Abstract]

D. R. Croucher, M. Iconomou, J. F. Hastings, S. P. Kennedy, J. Z. R. Han, R. F. Shearer, J. McKenna, A. Wan, J. Lau, S. Aparicio, D. N. Saunders, Bimolecular complementation affinity purification (BiCAP) reveals dimer-specific protein interactions for ERBB2 dimers. Sci. Signal.9, ra69 (2016). [Abstract]

M. A. Smith, R. Hall, K. Fisher, S. M. Haake, F. Khalil, M. B. Schabath, V. Vuaroqueaux, H.-H. Fiebig, S. Altiok, Y. A. Chen, E. B. Haura, Annotation of human cancers with EGFR signaling–associated protein complexes using proximity ligation assays. Sci. Signal  8, ra4 (2015). [Abstract]