Cellular Networks in Cancer
63 members representing 19 departments and centers at UT Southwestern
The Cellular Networks in Cancer (CNC) Program is a scientifically rich, collaborative, and productive research program. The vision of the Program is to advance the fundamental knowledge of both intercellular and intracellular networks that contribute to cancer initiation, tumorigenesis, and metastasis, then to translate these findings into novel approaches to cancer prevention and therapy. CNC’s overarching scientific goal is to promote discoveries in how perturbation in these cellular networks contribute to altered tissue physiology and promote cancer. The Program provides a highly interactive research environment that capitalizes on the UT Southwestern Medical Center’s longstanding tradition of basic science discoveries and fosters translation of these discoveries into the development of new biomarkers, diagnostic technologies, and therapeutic interventions in clinical oncology-especially malignancies relevant to the Simmons’ catchment area.
The program’s structure is purposefully designed to stimulate interdisciplinary intra- and interprogrammatic collaborations with the objective of delivering transformative discoveries. To accomplish this, four vibrant and synergistic subprograms were established that deliberately align with the strengths of program members and specifically relate to states of perturbed tissue homeostasis in cancer: Signaling and Cell Biology; Epigenetics and Gene Regulation; Immunobiology; and Metabolism.
Define Tumor Cell-Autonomous and Intercellular Mechanisms of Tumorigenesis
HIF-2 antagonism in kidney cancer
UT Southwestern’s Kidney Cancer SPORE, led by James Brugarolas, M.D., Ph.D., is an intra- and interprogram project comprising a large team of scientists and clinicians focused on understanding mechanisms of tumorigenesis in the kidney and identifying opportunities for intervention. The Kidney Cancer SPORE, which arose from this Program, has produced a number of high-impact papers and, increasingly, translational efforts. In a landmark 2016 study, the Brugarolas laboratory in collaboration with key partners in industry (Peloton Therapeutics) demonstrated the efficacy of hypoxia-inducible factor-2 (HIF-2) inhibition in clear cell renal cell carcinomas (ccRCCs).
Identify the Processes that Contribute to Tumor Evolution and Metastasis
Metabolic heterogeneity confers differences in melanoma metastatic potential
In a study, Ralph DeBerardinis, M.D., Ph.D, and a Simmons team determined that lactate, long considered a metabolic waste in cancer cells, is a prominent fuel in human NSCLCs in vivo, particularly in tumors displaying early progression and metastasis. This finding suggested that blocking lactate transport might suppress metastasis. In a reverse translation of these findings into tractable models, Sean Morrison, Ph.D., in collaboration with DeBerardinis, showed that lactate transport also predicts metastatic efficiency in patient-derived melanoma xenografts (PDXs), and that lactate transport genetically or with a monocarboxylate transporter-1 (MCT1) inhibitor suppressed metastasis, despite having minimal impact on tumor growth at the primary site.
Foster Interdisciplinary Interactions to Identify Interventions that Prevent Cancer Progression in Patients
Treating cancer by stimulating cGAS-mediated innate immune responses
Zhijian “James” Chen, Ph.D. groundbreaking work in mechanisms of innate immunity, particularly his discovery of the cyclic GMP-AMP synthase (cGAS)-STING pathway of cytosolic DNA sensing, has transformed our understanding of how cells activate interferon responses when confronted with exogenous and self-derived DNA in the cytosol. This discovery was awarded the 2019 Breakthrough Prize in Life Sciences. The cGAS-STING pathway was quickly established as a major player in immune responses against a variety of pathogens, and is now thought to have substantial relevance to DNA-damage responses in cancer as well.
Notable Publications
Conrad, L.B. et al. ADP-ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers. Molecular Cancer Therapeutics 2019; In press.
Courtney, K.D. et al. Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2alpha Antagonist in Patients with Previously Treated Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol 2018; 36: 867-74. PMCID: PMC5946714.
Formisano, L. et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun 2019; 10: 1373. PMCID: PMC6435685.
Hensley, C.T. et al. Metabolic Heterogeneity in Human Lung Tumors. Cell 2016; 164: 681-94. PMCID: PMC4752889.
Liu, Z. et al. A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-kappaB. Nature 2019; 568: 249-53. PMCID: PMC6812682.
Leadership
Ralph DeBerardinis, M.D., Ph.D.
Professor, Children’s Medical Center Research Institute at UT Southwestern
