Jason Heaney, Ph.D.
Assistant Professor of Molecular and Human Genetics
B.S., University of New Hampshire, 1998
Ph.D., Pennsylvania State University, 2004
Postdoc, Case Western Reserve University, 2010
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 recently 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 (Nanog and SOX2 expression), and prematurely express genes associated with meiotic differentiation (cyclin D1 and Stra8). Continued expression of both pluripotency and differentiation-associated genes through E15.5 is directly related with germ cell transformation into EC cells. Ongoing studies are using (1) knockout and overexpressing mouse models and developmental and genomic approaches to test how cyclin D1 and Stra8 promote TGCT initiation in mice, and (2) in vitro and in situ assays to test cyclin D1’s contribution to human EC cells tumorigenic potential and chemoresistance to cisplatin.
How does IL-33-mediated signaling contribute to intestinal cancer susceptibility?
We recently started testing whether genetic modifiers of TGCTs also influence adenoma risk in the ApcMin mouse model of colorectal cancer. We have found that one TGCT modifier, the Chr19MOLF/Ei chromosome substitution, increases intestinal polyp burden in APCMin mice. Using segregating crosses and congenic mice, we are identifying regions of chromosome 19 that harbor modifiers of adenoma risk. One candidate modifier, interleukin 33 (Il33), is a duel-function transcription factor and pro-inflammatory cytokine produced by intestinal epithelial cells (IECs) in response to infection and tissue damage. As a cytokine IL-33 signals through the IL1RL1 receptor in a variety of cell types to stimulate pro-inflammatory cytokine release in the intestine. The resulting inflammation stimulates a tissue repair response in IECs, which includes increased proliferation. Importantly, induction of IEC proliferation by inflammation is proposed to promote the neoplastic transformation of IECs. We recently discovered that adenoma-associated IECs in APCMin mice express high levels of IL33. We also discovered that intestinal subepithelial myofibroblasts (ISEMFs), which secrete factors into the intestinal stem cell niche to activate IEC tissue repair responses, and mast cells, which participate in type 2 helper T cell-mediated inflammatory responses, express IL1RL1 at the sites of adenoma growth in APCMin mice. Importantly, an antagonist antibody against IL1RL1 significantly reduces APCMin adenoma burden, suggesting that IL-33 signaling is a mediator of intestinal cancer risk. Ongoing studies are using genetic and genomic approaches to test whether (1) IL-33 signaling through mast cell and/or ISEMFs influences adenoma risk, (2) nuclear IL-33 functions as a transcriptional regulator in IECs, and (3) IL-33 mediates inflammation and increased colorectal cancer risk associated with high fat diets.
- 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 Genet. 14: 54. PubMed PMID: 23773267
- 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. Proc. Natl. Acad. Sci. U S A 109(41): E2766-73. PubMed PMID: 22923694
- Heaney JD, Anderson EL, Michelson MV, Zechel JL, Conrad PA, Page DC, Nadeau JH (2012). Germ cell pluripotency and premature differentiation influence testicular teratoma susceptibility in mice. Development 139(9): 1577-1586. PubMed PMID: 22438569
- Zechel JL, MacLennan GT, Heaney JD, Nadeau JH (2011). Spontaneous metastasis in mouse models of testicular germ-cell tumours. Int. J. Androl. 34(4 Pt 2): e278-287. PubMed PMID: 21651572
- Zhu R, Heaney JD, Nadeau JH, Ali S, Matin A (2010). Deficiency of splicing factor (SF1) suppresses occurrence of testicular germ cell tumors. Cancer Res. 70(18): 7264-7272. PubMed PMID: 20736371
- Heaney JD, Michelson MV, Youngren KK, Lam MJ, Nadeau JH (2009). Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice. Hum. Mol. Genet. 18(8): 1395-1404. PubMed PMID: 19168544
- Heaney JD, Lam MJ, 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 Res. 68(13): 5193-7. PubMed PMID: 18593919
- Lam MJ, Heaney JD, Youngren KK, Kawasoe JH, Nadeau JH (2007). Trans-generational influences on susceptibility to testicular germ cell tumors in interaction tests between Dnd1Ter and other modifier genes. Hum. Mol. Genet. 16(18): 2233-2240. PubMed PMID: 17616517
Jason Heaney, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza
Mail Stop: BCM227
Houston, TX, 77030, U.S.A.