Development and Cancer

Mission

To conduct studies at the intersection of developmental biology and cancer biology using cell-based models and whole organisms.

Overview

Hepatocellular carcinoma
LIN28B overexpression is sufficient to initiate hepatocellular carcinoma in mouse models; above, H&E staining of ApoE-LIN28B tumor tissue, with normal tissue at top left (see Nguyen et al., 2014).

The Development and Cancer Program explores the role of aberrant development in the genesis of cancer. The Program includes both laboratory researchers and physician-scientists, and features 40 members from 17 departments, including scientists from the fields of cancer, stem cell, and developmental biology. Program members investigate the developmentally and evolutionarily conserved ancestral themes that are fundamental to cell and organism growth, development, and physiology, and how these factors influence cancer biology.

Themes

  • Tumor-stroma interactions
  • Cancer cell programming
  • Epigenetics and cell fate
  • Stem cell biology

Research Highlights

Proton magnetic resonance spectroscopy provides noninvasive evaluation of 2-hydroxyglutarate in IDH1-mutated gliomas.
Proton magnetic resonance spectroscopy provides noninvasive evaluation of 2-hydroxyglutarate in IDH1-mutated gliomas (see Choi et al., 2012).

Imaging the glioma biomarker 2HG. Research spearheaded by Development and Cancer (and involving collaborations across the Cancer Center) has revealed that the metabolite 2-hydroxyglutarate (2HG), which accumulates in gliomas as a result of mutations in the genes IDH1 and IDH2, is detectable with magnetic resonance spectroscopy. The finding represents a novel example of a noninvasive imaging biomarker directly linked to a genetic mutation in a cancer cell. In a phase I/II clinical trial at UT Southwestern of a first-in-class IDH2 inhibitor, the approach is being used to provide a direct readout of IDH inhibition.

 

Cancer Center researchers have developed zebrafish models of malignant germ cell tumor and Ewing sarcoma.
Cancer Center researchers have developed zebrafish models of malignant germ cell tumor and Ewing sarcoma (see Neumann et al., 2011; Leacock et al., 2012).

Molecularly targeted therapy for soft-tissue sarcoma. A $6.9 million grant from the Cancer Prevention and Research Institute of Texas is fueling a multi-investigator, multi-institution research project to conduct molecular genetics and functional genomics studies in soft-tissue and Ewing sarcoma. The project aims to uncover unknown drivers of soft-tissue sarcoma, with the goal of developing molecularly targeted therapies. The effort includes a biospecimen banking initiative encompassing patients at cancer centers across Texas, and builds upon UT Southwestern research developing unique, non-mammalian models of human cancer, including a Drosophila (fruit fly) model of rhabdomyosarcoma, and zebrafish models of malignant germ cell tumor and Ewing sarcoma.

To Get Involved

The Program welcomes additional physicians and scientists seeking a broader and deeper understanding of how developmental processes go awry to contribute to cancer development or progression.

Topics of interest include, but are not limited to, stem cell biology, and mechanisms of lineage commitment and cellular differentiation; heterotypic cell-cell interactions in tissue/organ formation and tumor-stroma interactions; immunobiology and therapeutics of human cancer; cellular metabolism and development; and transcriptional and post-transcriptional control of gene and protein synthesis.

Contact Dr. Skapek for more details about the Development and Cancer Program, meetings, and more. stephen.skapek@utsouthwestern.edu

Selected Publications

Carreira-Rosario, A. et al. Repression of Pumilio protein expression by Rbfox1 promotes germ cell differentiation. Dev Cell 36, 562-71 (2016).

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

Choi, C. et al. Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma. J Clin Oncol 34, 4030-9 (2016).

DeNicola, G.M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet 47, 1475-81 (2015).

Guo, Y. et al. Comprehensive ex vivo transposon mutagenesis identifies genes that promote growth factor independence and leukemogenesis. Cancer Res 76, 773-86 (2016).

Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017).

Hensley, C.T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681-94 (2016).

Hoang, C.Q. et al. Transcriptional maintenance of pancreatic acinar identity, differentiation and homeostasis by PTF1A. Mol Cell Biol 6, 3033-3047 (2016).

Inra, C.N. et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466-71 (2015).

Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255-8 (2016).

Kang, X. et al. Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors. Cell Cycle 15, 25-40 (2016).

Lee, E. et al. Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis. Oncotarget 7, 67919-67933 (2016).

Lee, S. et al. Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell 164, 69-80 (2016).

Liang, C. et al. TAF11 assembles the RISC loading complex to enhance RNAi efficiency. Mol Cell 59, 807-18 (2015).

Lu, Z. et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med 23, 79-90 (2017).

Ma, G. et al. Regulation of smoothened trafficking and Hedgehog signaling by the SUMO pathway. Dev Cell 39, 438-451 (2016).

Matsui, T. et al. Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids. Development 144, 1025-34 (2017).

Mottier-Pavie, V.I. et al. The Wnt pathway limits BMP signaling outside of the germline stem cell niche in Drosophila ovaries. Dev Biol 417, 50-62 (2016).

Nguyen, L.H. et al. Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell 26, 248-261 (2014).

Pena, C.G. et al. LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment. J Clin Invest 125, 4063-76 (2015).

Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-91 (2015).

Rakheja, D. et al. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat Commun 2, 4802 (2014).

Signer, R.A. et al. The rate of protein synthesis in hematopoietic stem cells is limited partly by 4E-BPs. Genes Dev 30, 1698-703 (2016).

Singh, D.K. et al. Oncogenes activate an autonomous transcriptional regulatory circuit that drives glioblastoma. Cell Rep 18, 961-76 (2017).

Sun, X. et al. Suppression of the SWI/SNF component Arid1a promotes mammalian regeneration. Cell Stem Cell 18, 456-66 (2016).

Wang, L.L. et al. The p53 pathway controls SOX2-mediated reprogramming in the adult mouse spinal cord. Cell Rep 17, 891-903 (2016).

Wei, W. et al. Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects. Cell Metab 23, 479-91 (2016).

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

Wylie, A. et al. p53 genes function to restrain mobile elements. Genes Dev 30, 64-77 (2016).

Xu, L. et al. Potential pitfalls of mass spectrometry to uncover mutations in childhood soft tissue sarcoma: a report from the Children's Oncology Group. Sci Rep 6, 33429 (2016).

Zeitels, L.R. et al. Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis. Genes Dev 28, 2585-2590 (2014).

Zhou, Z. et al. Deubiquitination of Ci/Gli by Usp7/HAUSP regulates Hedgehog signaling. Dev Cell 34, 58-72 (2015).