Jan van Riggelen's Lab Page

The van Riggelen laboratory studies the epigenetic aspect of self-renewal and cellular differentiation in cancer using cell and molecular biology approaches. In particular, we are interested in how the functional properties of transcription factors that determine cell fate are dependent on the epigenetic state of the cell. 

 Jan van Riggelen, PhD – Assistant Professor

Biochemistry and Molecular Biology Department, Member Augusta University Cancer Center and College of Graduate Studies

Dr. van Riggelen received his PhD from the Ruprecht-Karls University of Heidelberg, Germany for his work at the German Cancer Research Center (DKFZ) with Frank Roesl, PhD and Harald zur Hausen, MD (Nobel Laureate 2008). Before he came to Augusta University in 2012 he trained as postdoctoral fellow at Stanford University with Dean W. Felsher, MD, PhD.

Email: jvanriggelen at gru.edu

Wenli Yama Zheng, PhD – Postdoctoral Fellow

Dr. Zheng received her PhD from the Chinese University of Hong Kong in 2010 for her work with Yuk Ming Dennis Lo, PhD. She joined the lab in 2013.

Email: wezheng at gru.edu

Haesung Lee, BS – Medical Student at PCOM

Haesung received her BS in Biochemistry and Molecular Biology from the University of Georgia, Athens, GA USA in 2013. Haesung worked as research assistant in lab from 2013-2014. In 2014 she started medical school at PCOM and continues her project in lab as student.

Email: halee at gru.edu

Danielle DeFoe, BS – Medical Student at MCG

Danielle received her BS with Honors in Genetics from the University of Georgia, Athens, GA USA in 2012. Danielle worked as research assistant in lab from 2012-2013. In 2013 she started medical school at MCG and continues her project in lab as student.

Email: ddefoe at gru.edu

Senescence as barrier for tumorigenesis

Tumorigenesis is a multi-step process driven by genetic and epigenetic changes in oncogenes and tumor suppressor genes. These sequential alterations are thought to promote distinct steps in the progression of normal cells to full malignancy.

One of the key steps during tumorigenesis is ability to bypass the mechanisms that limit the lifespan of normal cells and enable tumor cells to proliferate indefinitely. In order to gain immortality cells have to overcome an irreversible growth-arrest termed cellular senescence, which functions as fail-safe mechanism for uncontrolled proliferation and barrier for tumorigenesis. Hence, the mechanisms eliciting oncogene-induced senescence were believed to be permanently deactivated in cancer cells.

Cellular senescence as key mechanism for tumor regression upon oncogene inactivation

Recent evidence, however, indicates that the signaling pathways responsible for inducing cellular senescence in normal cells are not permanently silenced in tumor cells. We and others showed in a variety of different tumor types, that the fail-safe mechanism of cellular senescence can be reactivated by either restoring a tumor suppressor function such as p53 (Martins et al. Cell 2006; Venture et al. Nature 2007) or inactivating a single oncogene such as c-Myc.

In fact, cellular senescence is the key mechanism to induce tumor regression upon inactivation of the c-Myc oncogene. We found that in T-cell acute lymphoblastic leukemia (T-ALL) the transforming growth factor (TGF)-beta pathway is constitutively active and forms an autocrine feedback loop that is required to induce cellular senescence and sustained tumor regression upon c-Myc inactivation.

The epigenetic aspect of self-renewal and cellular differentiation in cancer

Currently, the van Riggelen laboratory uses the Myc/Miz1 network and Smad/TGF-beta signaling pathway in hematopoietic malignancies as a model system to study how dynamics in the epigenetic landscape affect the properties of key transcriptional regulators to drive proliferation vs. cellular senescence. Conversely, we are interested in how these transcription factors themselves determine the cellular phenotype by altering chromatin structure on a genome-wide level. The main focus is on spatial and temporal control of DNA methyltransferase (Dnmt) activity and dynamics of genome-wide DNA methylation through c-Myc.

Key References:

Wu AR, Kawahara TL, Rapicavoli NA, van Riggelen J, Shroff EH, Xu L, Felsher DW, Chang HY, Quake SR. High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation. Lab Chip. 2012 Jun 21;12(12):2190-8. Epub 2012 May 8.

Choi PS, van Riggelen J, Gentles AJ, Bachireddy P, Rakhra K, Adam SJ, Plevritis SK, Felsher DW. Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction. Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17432-7. Epub 2011 Oct 3.

Müller J, Samans B, van Riggelen J, Fagà G, Peh K N R, Wei CL, Müller H, Amati B, Felsher D, Eilers M. TGFβ-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages in Myc-induced lymphomas. Cell Cycle. 2010 Dec 1;9(23):4622-6.

van Riggelen J, Müller J, Otto T, Beuger V, Yetil A, Choi PS, Kosan C, Möröy T, Felsher DW, Eilers M. The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev. 2010 Jun 15;24(12):1281-94.

van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010 Apr;10(4):301-9. Review.

van Riggelen J, Felsher DW. Myc and a Cdk2 senescence switch. Nat Cell Biol. 2010 Jan;12(1):7-9. Review.

Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13028-33. Epub 2007 Jul 30.

Giuriato S, Ryeom S, Fan AC, Bachireddy P, Lynch RC, Rioth MJ, van Riggelen J, Kopelman AM, Passegué E, Tang F, Folkman J, Felsher DW. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16266-71. Epub 2006 Oct 20.