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Development and Cancer

39 members representing 18 departments at UT Southwestern

The multidisciplinary Development and Cancer (DC) Program is unique among Simmons programs in that its members investigate the developmentally and evolutionarily conserved processes that are fundamental to cancer cell growth, division, and differentiation. DC investigators also study the organ and organism growth and developmental processes that are derailed in human cancer.

The DC Program members pursue four major aims to cover the diversity at the developmental and cancer biology interface: Systematic analyses of stem cell biology and regeneration; Exploring gene expression and cell fate; Studies of cell differentiation and organogenesis; and Analyzing cell–cell and cell–stroma interactions.

Systematic Analyses of Stem Cell Biology and Regeneration

Metabolic vulnerabilities of HSCs and metastatic melanoma cells

The extent to which physiological variations in metabolites influence stem cell function and tissue regeneration in cancer is poorly understood. To address this question, researchers in the Morrison laboratory teamed up with Ralph DeBerardinis, M.D., Ph.D., and Michail Agathocleous, Ph.D., to optimize the sensitivity of metabolomics methods, thus enabling the analysis of rare cell populations. This groundbreaking technology was used to compare metabolite levels between hematopoietic stem cells (HSCs) and a wide range of restricted hematopoietic progenitors isolated from mouse bone marrow. The team found that human and mouse HSCs are distinguished from most other hematopoietic cells by unusually high levels of ascorbate (vitamin C).

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Exploration Gene Expression and Cell Fate

Transcriptional regulators that control the fate of myoblasts in rhabdomyosarcoma

Deregulation of developmental processes lie at the heart of many forms of childhood cancer. Development and Cancer Program researchers study subjects directly relevant to a variety of childhood tumors, including acute leukemia, childhood kidney cancer, and forms of childhood brain tumor. Previously, Eric Olson, Ph.D., and members of his laboratory reported that expression of the TWIST2 transcription factor defines a unique muscle progenitor cell. Collaborating with Stephen Skapek, M.D., the Olson group showed that knockdown of TWIST2 in human RMS cells induces the expression of myogenin.

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Studies of Cell Differentiation and Organogenesis

Somatic mutations in liver regeneration

The Zhu lab is focused on the relationship between regeneration and cancer. Particularly, they’re interested in how cancer genes influence normal liver cell biology prior to transformation. A recent collaboration between the Zhu lab and Simmons Cancer Center members Sam Wang, M.D., Tao Wang, Ph.D., Adam Yopp, M.D., and Amit Singal, M.D., identified a broad range of recurrent mutations in chronically diseased livers to clonal expansion were not always driving early cancer events.

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Analysis of Cell-Cell and Cell-Stroma Interactions

Immune inhibitory receptor signaling

To study leukocyte Ig-like receptor subfamily B (LILRB) function in cancer and develop novel anticancer strategies, Alec Zhang, Ph.D., collected blood and tumor samples from a variety of cancer types, including leukemia and solid cancers such as breast, ovarian, prostate and melanoma. In collaboration with Robert Collins, M.D., Weina Chen, M.D., Ph.D., and Yang-Xin Fu, Ph.D., they demonstrated that LILRB proteins, most notably LILRB4, promotes leukemia by suppressing anti-tumor T cell activity.

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Notable Publications

Borromeo, M.D. et al. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell Rep 2016; 16: 1259-72. PMCID: PMC4972690.

Updegraff, B.L. et al. Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism. Cell Rep 2018; 25: 2223-33 e6. PMCID: PMC6338450.

Bu, D. et al. Human endotrophin as a driver of malignant tumor growth. JCI Insight 2019; 5. PMCID: PMC6538351.

Skapek, S.X. et al. Rhabdomyosarcoma. Nat Rev Dis Primers 2019; 5: 1.

Chen, K.S. et al. Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1. Genes Dev 2018; 32: 996-1007. PMCID: PMC6075147.

Leadership

Joshua Mendell, M.D., Ph.D.

Professor, Molecular Biology

Mendell Lab

Joshua Mendell, M.D., Ph.D.

Stephen X. Skapek, M.D.

Professor, Pediatrics

Skapek Lab

Stephen Skapek, M.D.