Cancer Cell Networks


To promote research that will contribute to an understanding of the mechanisms at work in aberrant cell regulatory networks that support cancer initiation and growth.


Activation of autophagy in cells from the lung cancer cell line HCC827 upon treatment with the EGFR inhibitor erlotinib.

The Cancer Cell Networks Program facilitates investigations that shed light on the mechanisms by which aberrant cell regulatory networks support the initiation of cancers. Program members’ approaches range from structural biology to animal models.

Cancer Cell Networks has 45 members representing 14 departments and centers. Key goals of the program are to define mechanisms and pathways that integrate external and internal regulatory cues at the cell autonomous level; determine how aberrant cell regulation contributes to the transformation of normal cells to cancer cells; and to engage translational and clinical scientists in investigating whether modulating specific aspects of cell regulation has therapeutic potential against cancer.


  • Chromatin regulation
  • Autophagy
  • G protein signaling
  • Organelle communication
  • Stem cells
  • RNA processing
  • Inflammation
  • Metabolism

Research Highlights

Map depicts a human gene regulatory subnetwork (blue), connected to miRNAs (red) and chemical compounds (green) (see Potts et al., 2013).

Functional Signature Ontology (FUSION). This novel technique, developed in a cross-disciplinary initiative led by Michael White, Ph.D., and John MacMillan, Ph.D., is using cell-based screening and computational analysis to comprehensively identify both promising cancer-fighting chemicals derived from natural marine products and, concurrently, the proteins or biological processes they act on in cells. The technique uses libraries of small interfering RNAs and synthetic microRNAs, whose targets in cells are known, as a Rosetta stone, allowing researchers to match gene expression patterns from the library molecules with those of the marine-derived chemicals. From that, the scientists can infer whether and exactly how the most promising chemicals exert anti-cancer effects.

Cyclic GMP-AMP (cGAMP), an immune booster (see Sun et al., 2013)

The cGAS-STING pathway of innate immunity. Zhijian “James” Chen, Ph.D., and colleagues are shedding new light on our understanding of innate immune responses to DNA and RNA. Combining classical protein purification with quantitative mass spectrometry, the researchers have discovered a new enzyme, cyclic GMP-AMP synthase (cGAS), that acts as a sensor of innate immunity – the body’s first line of defense against invaders.

The work also has described a novel cell signaling pathway: When cGAS detects foreign DNA or even host DNA that is in the cell’s cytoplasm, the enzyme binds to the DNA, catalyzing formation of a chemical called cyclic GMP-AMP, or cGAMP, a naturally occurring compound in a class known to exist in bacteria but never before seen in multicellular organisms. Then cGAMP binds to the protein STING, activating a signaling cascade that produces interferons and pro-inflammatory cytokines.

In addition to demonstrating the pathway’s significance in innate immune defense and in autoimmune diseases, Dr. Chen’s lab has shown that cGAMP can increase antibody production and T-cell activation, highlighting a potential role in boosting anti-tumor immunity and developing cancer vaccines.

To Get Involved

The program seeks additional physicians and scientists to further collaboration focusing on large-scale, unbiased interrogation of cancer cell regulatory systems based on established RNAi high-throughput screening and to leverage results from functional genomics efforts.

For details about the program, information on subgroup meeting times and locations, and more, contact Dr. Cobb or Dr. Scaglioni.

Program meetings are attended by all investigators, postdoctoral fellows, students, and scientist-level technical staff. In particular, students from the Cancer Biology Ph.D. Program participate in the regular program meetings as a component of their weekly W.I.P., or Work In Progress.

Selected Publications

Augustyn, A. et al. ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proc Natl Acad Sci USA 111, 14788-14793 (2014).

Avirneni-Vadlamudi, U. et al. Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma. J Clin Invest 122, 403-407 (2012).

Bodemann, B.O. et al. RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144, 253-267 (2011).

Brugarolas, J. Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol 32, 1968-1976 (2014).

Chen, B. et al. The WAVE regulatory complex links diverse receptors to the actin cytoskeleton. Cell 156, 195-207 (2014).

Eliazer, S. et al. Lsd1 restricts the number of germline stem cells by regulating multiple targets in escort cells. PLoS Genet 10, e1004200 (2014).

Gagnon, K.T. et al. RNAi factors are present and active in human cell nuclei. Cell Rep 6, 211-221 (2014).

Gao, D. et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341, 903-906 (2013).

Hao, Y.H. et al. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell 152, 1051-1064 (2013).

He, C. et al. Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154, 1085-1099 (2013).

He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511-515 (2012).

Hou, F. et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448-461 (2011).

Kim, H.S. et al. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155, 552-566 (2013).

Konstantinidou, G. et al. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov 3:444-57 (2013).

Li, X.D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390-1394 (2013).

Mender, I. et al. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine. Cancer Discov 5, 82-95 (2015).

Osborne, J.K. et al. NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas. Mol Biol Cell 25, 1782-1792 (2014).

Ou, Y.H. et al. TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol Cell 41, 458-470 (2011).

Pavia-Jimenez, A. et al. Establishing a human renal cell carcinoma tumorgraft platform for preclinical drug testing. Nat Protoc 9, 1848-1859 (2014).

Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44, 751-759 (2012).

Ram, R.R. et al. RASSF1A inactivation unleashes a tumor suppressor/oncogene cascade with context-dependent consequences on cell cycle progression. Mol Cell Biol 34, 2350-2358 (2014).

Schuster, K. et al. Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Mol Cancer Res 12, 912-923 (2014).

Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201-206 (2013).

Sivanand, S. et al. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci Transl Med 4, 137ra75 (2012).

Srivastava, N. et al. Inhibition of cancer cell proliferation by PPARgamma is mediated by a metabolic switch that increases reactive oxygen species levels. Cell Metab 20, 650-661 (2014).

Tang, Z. et al. Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature 502, 254-257 (2013).

Wang, R.C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956-959 (2012).

Wang, S. et al. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc Natl Acad Sci USA 111, 4251-4256 (2014).

Wei, Y. et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 1269-1284 (2013).

Wong, M.S. et al. Regulation of human telomerase splicing by RNA:RNA pairing. Nat Commun 5, 3306 (2014).