Timothy Hallstrom

Associate Professor

Department of Pediatrics

Medical School

The Hallstrom laboratory is studying the cellular mechanisms controlling Rb/E2F induced apoptosis during normal proliferation and in cancer development. Normal cellular proliferation is tightly regulated by cell size, mitogenic stimulation, and the absence of signals that block proliferation.

The retinoblastoma (Rb) protein is a pivotal regulator of entry into the cell cycle and, importantly, disruption of various components of this control pathway leads to deregulated proliferation that underlies the development of many forms of cancer. Rb regulation of cell cycle progression and tumorigenesis is dependent on its control of E2F transcription factor function, a family of proteins that control the expression of genes required for proliferation.

Further work has highlighted the role of E2F proteins, particularly E2F1, in forming the link between the deregulation of Rb pathway activity and induction of p53-dependent apoptosis. E2F1 apoptosis induction is believed to serve a tumor-suppressive mechanism by eliminating cells that have sustained an oncogenic mutation which activates the Rb pathway.

Research Summary / Interests

Immune Response in Pediatric Retinoblastoma Tumors

Our research interests focus on two major areas. The first is on the pediatric cancer retinoblastoma, which forms in the retina of children and infants. This cancer is caused by deregulation of the Rb/E2F pathway. We developed a novel mouse retinoblastoma model that develops rapid bilateral tumors in both eyes. Recently, we learned that these tumors express a gene expression “signature” that causes recruitment and accumulation of immune cells to these tumors. Since this is a highly sought-after clinical goal, we are elucidating the mechanisms of immune cell recruitment so they can be targeted to kill cancer cells.

Epigenetics of Retinal Development

The second major research interest is in the epigenetic control mechanisms responsible for normal retinal development. These mechanisms can malfunction in pediatric retinoblastoma and may be harnessed during retinal regeneration to produce new retinal cell types after they’ve been lost. In particular, we study the retinal function of an epigenetic regulator called UHRF2, which binds to a DNA epigenetic base called 5-hydroxymethylcytosine (5hmC). It is still poorly understood how 5hmC accumulates during retinal development and how this leads to proper retinal gene expression. Furthermore, 5hmC is widely lost in human tumors, including retinoblastoma, although the mechanism behind its loss is unclear, as is the anti-tumor effectiveness of restoring 5hmC. We utilize genome-wide approaches to understand the altered gene expression and 5hmC distribution in retinal cells lacking the Uhrf2 gene.


Sarver AL, Xie C, Riddle MJ, Forster CL, Wang X, Lu H, Wagner W, Tolar J, Hallstrom TC. (2021) “Retinoblastoma tumor cell proliferation is negatively associated with immune-modulatory signals and immune infiltration”. Under revision, Lab Investigation.

Wang X. Sarver AL, Lu H, Xie C, Forster CL, Hallstrom TC. (2021) Reduced TET expression and 5hmC levels delay neural progenitor cell cycle progression and differentiation in Uhrf2 mutant retina. Under revision, Development.

Xie C, Freeman MJ, Forster CL, Hallstrom TC. (2017) “Retinoblastoma cells activate the AKT pathway and are vulnerable to anti-PI3K/mTOR therapeutics” Oncotarget.doi: 10.18632/oncotarget.16970.

Lu H, Bhoopatiraju S, Wang H, Schmitz NP, Forster CL, Verneris MR, Linden MA and Hallstrom TC. (2016) Loss of UHRF2 expression is associated with human neoplasia, promoter hypermethylation, decreased 5-hydroxymethylcytosine, and high proliferative activity. Oncotarget. 7(46):76047-76061.

Filtz EA, Emery A, Lu H, Forster CL, Karasch C, Hallstrom TC. (2015) Rb1 and Pten co-deletion in osteoblast precursor cells causes rapid lipoma formation in mice. PLOS ONE.10(8):e0136729. doi: 10.1371/journal.pone.0136729. eCollection 2015.

Xie C, Lu H, Nomura A, Hanse EA, Forster CL, Parker JB, Linden MA, Karasch C, Hallstrom TC. (2015) Co-deleting Pten with Rb in retinal progenitor cells in mice results in fully penetrant bilateral retinoblastomas.Molecular Cancer. 14(1) 93.

Lu H, Hallstrom TC. (2013) The nuclear protein UHRF2 is a direct target of the transcription factor E2F1 in the induction of apoptosis. J Biol Chem. 288(33):23833-43.