Cancer Cell Networks

Mission

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.

Overview

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.

Themes

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

Research Highlights

cGAMP
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.

FUSION
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.

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

Borromeo, M.D. et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep 16, 1259-1272 (2016).

Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112-117 (2016).

Chittajallu, D.R. et al. In vivo cell-cycle profiling in xenograft tumors by quantitative intravital microscopy. Nat Methods 12, 577-85 (2015).

Courtney, K.D. et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol 36, 867-874 (2018).

Danko, C.G. et al. Identification of active transcriptional regulatory elements from GRO-seq data. Nat Methods 12, 433-8 (2015).

Diao, J. et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520, 563-6 (2015).

Franco, H.L. et al. TNFα signaling exposes latent estrogen receptor binding sites to alter the breast cancer cell transcriptome. Mol Cell 58, 21-34 (2015)

Golden, R.J. et al. An Argonaute phosphorylation cycle promotes microRNA-mediated silencing. Nature 542, 197-202 (2017).

Gu, Y.F. et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov 7, 900-17 (2017).

Ji, Z. et al. Kinetochore attachment sensed by competitive Mps1 and microtubule binding to Ndc80C. Science 348, 1260-4 (2015).

Katafuchi, T. et al. Detection of FGF15 in plasma by stable isotope standards and capture by anti-peptide antibodies and targeted mass spectrometry. Cell Metab 21, 898-904 (2015).

Kim, J. et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 538, 114-117 (2016).

Liu, H. et al. Mitotic transcription installs Sgo1 at centromeres to coordinate chromosome segregation. Mol Cell 59, 426-36 (2015).

Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).

Luo, M. et al. A STING-activating nanovaccine for cancer immunotherapy. Nat Nanotechnol 12, 648-654 (2017).

Mager, L.F. et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J Clin Invest 125, 2579-91 (2015).

Mattila, J.P. et al. A hemi-fission intermediate links two mechanistically distinct stages of membrane fission. Nature 524, 109-113 (2015).

Maxfield, K.E. et al. Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer. Nat Commun 6, 8840 (2015).

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

Moretti, J. et al. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum. Cell 171, 809-823.e13 (2017).

Pineda, C.T. et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715-728 (2015).

Potts, M.B. et al. Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B. Nat Chem Biol 11, 401-8 (2015).

Shi, H. et al. Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING. Proc Natl Acad Sci USA 112, 8947-52 (2015).

Singh, D.K. et al. Oncogenes activate an autonomous transcriptional regulatory circuit that drives glioblastoma. Cell Rep 18, 961-976 (2017).

Sun, M. et al. Discovery, annotation, and functional analysis of long noncoding RNAs controlling cell-cycle gene expression and proliferation in breast cancer cells. Mol Cell 59, 698-711 (2015).

Wang, H. et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc Natl Acad Sci USA 114, 1637-1642 (2017).

Wei, J.H. et al. GM130 regulates Golgi-derived spindle assembly by activating TPX2 and capturing microtubules. Cell 162, 287-299 (2015).

Wei, Y. et al. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168, 224-238.e10 (2017).

Westcott, J.M. et al. An epigenetically distinct breast cancer cell subpopulation promotes collective invasion. J Clin Invest 125, 1927-43 (2015).

Witkiewicz, A.K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun 6, 6744 (2015).

Xu, M.M. et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein α signaling. Immunity 47, 363-373.e5 (2017).

Yu, C.H. et al. Codon usage influences the local rate of translation elongation to regulate co-translational protein folding. Mol Cell 59, 744-54 (2015).