Assistant Professor, Baylor College of Medicine
Ph.D., University of Wisconsin, Madison, 2001
Postdoc, University of Wisconsin, Madison, 2001-03
Postdoc, Princeton University, 2003-09
Testicular and colon cancer genetics; Stem/progenitor cell maintenance; Mouse models of human diseases; Genome editing technologies
In my laboratory we use mouse genetics and genomics to identify genes and pathways involved in the neoplastic transformation of stem/progenitor cells. Our overall goal is to utilize knowledge gained from our mouse models to understand the causes of tumor initiation in humans and to provide new targets for the early diagnosis and treatment of cancer. Ongoing research is focused on two questions:
What genes and developmental pathways contribute to testicular germ cell tumor (TGCT) initiation?
Male germ cell development in the 129 family of inbred mice is an important in vivo experimental model system for studying fundamental questions about maintenance of pluripotency and induction of differentiation. Germ cells arise during embryogenesis as pluripotent primordial germ cells (PGCs) that differentiate into mature gametes and ultimately the cells and tissues of an adult organism. Defects during male germ cell development can lead to the formation of testicular germ cell tumors (TGCTs). In 129 mice, TGCTs arise during embryonic days (E)13.5-15.5 as foci of pluripotent embryonal carcinoma cells (EC cells), which differentiate to form teratomas. At E13.5, male germ cells normally enter mitotic arrest until after birth and female germ cells initiate the meiotic program, both of which are accompanied by down-regulation of pluripotency. We have identified a defect in this developmental switch as the cause of TGCT initiation. In TGCT susceptible gonads, germ cells fail to enter mitotic arrest, retain pluripotency, and misexpression genes associated with male and female germ cell differentiation. Ongoing studies are using novel genetically engineered mouse models created with CRISPR/Cas9 genome editing technology and in vitro and in situ assays to understand the genetics and developmental origins of TGCT susceptibility in 129 mice. Studies in the lab are determining how three genes (Ccnd1, Prdm14, and Eif2s2) and the cellular pathways in which they function (cell cycle progression, germ cell specification, and regulation of translation initiation) contribute to TGCT risk. Additional studies are using the 129 mouse model and CRISPR/Cas9 genome editing technology to functionalize human TGCT genome wide association study (GWAS) discoveries.
How does IL-33-mediated signaling contribute to intestinal cancer susceptibility?
Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by non-epithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. We have identify interleukin (IL)-33 as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 is expressed in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1, localizes to the stroma of adenomas and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the ApcMin mouse model of intestinal tumorigenesis reduces both tumor number and size. Similar to human adenomas, IL-33 expression localizes to tumor epithelial cells and expression of IL1RL1 associates with two tumor stroma cell types, subepithelial myofibroblasts (SEMFs) and mast cells, in ApcMin polyps. In vitro, IL-33 stimulation of human SEMFs induces the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduces mast cell accumulation in ApcMin polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Ongoing studies are using genetic and genomic approaches to test whether (1) IL-33 signaling through mast cells and/or SEMFs influences adenoma risk, (2) nuclear IL-33 functions as a transcriptional regulator in epithelial cells, and (3) nuclear or cytokine IL-33 promote colorectal cancer metastasis.
Lanza DG, Dawson EP, Rao P, Heaney JD (2016) Misexpression of cyclin D1 in embryonic germ cells promotes testicular teratoma initiation. Cell Cycle 15:919-930.
Maywald RL, Doerner SK, Pastorelli L, De Salvo C, Benton SM, Dawson EP, Lanza DG, Berger NA, Markowitz SD, Lenz HJ, Nadeau JH, Pizarro TT, Heaney JD (2015) IL-33 activates tumor stroma to promote intestinal polyposis. Proceedings of the National Academy of Sciences USA 112:E2487-E2496.
Zechel JL, Doerner SK, Lager A, Tesar PJ, Heaney JD, Nadeau JH (2013) Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis. BMC Genetics 14:54.
Nelson VR, Heaney JD, Tesar PJ, Davidson NO, Nadeau JH (2012) Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proceedings of the National Academy of Sciences USA 109:E2766-E2773.
Heaney JD, Anderson EL, Michelson MV, Zechel JL, Conrad PA, Page DC, Nadeau JH (2012) Germ cell pluripotency, premature differentiation and susceptibility to testicular teratomas in mice. Development 139:1577-1586.
Zhu R, Heaney J, Nadeau JH, Ali S, Matin A (2010) Deficiency of splicing factor 1 suppresses the occurrence of testicular germ cell tumors. Cancer Research 70:7264-7272.
Heaney JD, Michelson MV, Youngren KK, Lam MY, Nadeau JH (2009) Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice. Human Molecular Genetics 18:1395-1404.
Heaney JD, Lam MY, Michelson MV, Nadeau JH (2008) Loss of the transmembrane but not the soluble kit ligand isoform increases testicular germ cell tumor susceptibility in mice. Cancer Research 68:5193-5197.
Jason D. Heaney, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, Room R810
Houston, Texas 77030, U.S.A.
Tel: (713) 798-1778