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 2HGResearch 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 in 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.

Selected Publications

Asterholm, I.W. et al. Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell Metab 15, 171-185 (2012).

Baek, G. et al. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep 9, 2233-2249 (2014).

Buszczak, M. et al. Cellular differences in protein synthesis regulate tissue homeostasis. Cell 159, 242-251 (2014).

Chen, Z. et al. Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell 26, 695-706 (2014).

Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522-526 (2012).

Chivukula, R.R. et al. An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration. Cell 157, 1104-1116 (2014).

Choi, C. et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18, 624-629 (2012).

Fan, D. et al. Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization. Nat Med 21, 808-14 (2015).[KP5]

Hatley, M.E. et al. A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell 22, 536-546 (2012).

Krzeszinski, J.Y. et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature 512, 431-435 (2014).

Magee, J.A. et al. Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell 11, 415-428 (2012).

Mahajan, P. et al. PAX genes in childhood oncogenesis: developmental biology gone awry? Oncogene 34, 2681-2689 (2015).

Marin-Valencia, I. et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab 15, 827-837 (2012).

Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014).

Mo, W. et al. CXCR4/CXCL12 mediate autocrine cell-cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 152, 1077-1090 (2013).

Mullen, A.R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385-388 (2011).

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).

Park, J. et al. Neuregulin 1-HER axis as a key mediator of hyperglycemic memory effects in breast cancer. Proc Natl Acad Sci USA 109, 21058-21063 (2012).

Park, J., Scherer, P.E. Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest 122, 4243-4256 (2012).

Patel, A.J. et al. BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. Cell Rep 6, 81-92 (2014).

Pozo, K. et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24, 499-511 (2013). 

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

Shi, Q. et al. Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator. Proc Natl Acad Sci USA 111, E5651-E5660 (2014).

Signer, R.A. et al. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49-54 (2014).

Wu, Q. et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep 5, 637-645 (2013).

Yang, C. et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell 56, 414-424 (2014).

Yue, T. et al. The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Dev Cell 22, 255-267 (2012).

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

Zheng, J. et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656-660 (2012).

Zheng, J. et al. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell 9, 119-130 (2011).