Siyuan Zheng, Ph.D.
Rank: Assistant Professor
Department: Population Health Sciences
Our lab is located at the Greehey Cancer Research Institute (GCCRI), UT Health San Antonio. We use genomic and proteomic data to understand the mechanisms behind the initiation, progression, treatment responses of pediatric and adult cancers. Our research is focused on identifying aberrations in cancer, including single nucleotide variations, insertions, deletions, DNA and RNA structural rearrangements, DNA copy number alterations that facilitate the various aspect of the cancer ecosystem.
We welcome motivated researchers and students with similar interests to join our team!
Our primary tool to study cancer is high throughput data/assay, mostly DNA/RNA sequencing, and proteomics. These data allow us to identify driver genes, stratify molecular subtypes, and model significant events in cancer.
Example 1: mining the genome of glioblastoma. Glioblastoma, a.k.a GBM is a deadly brain tumor affecting ~10,000 people annually in the US. It is one of the cancers that did not see much outcome improvement in the last decade. On average, patients live with the disease for only 15 months, despite surgery, radiation, and chemo. Around 2012, we launched a study to investigate the copy number landscape of GBM, hoping to find a gene that has a similar genetic change to EGFR vIII, an essential signaling gene in controlling cell growth. Although we did find infrequent events like that, a surprising finding was frequent double minutes encompassing, thus co-amplifying two oncogenes CDK4 and MDM2, both closely localized to chr12q (Zheng et al. Genes Dev, 2013). This phenomenon was later confirmed by other groups and was thought to result from chromothripsis.
Example 2: integrative analysis of adrenocortical carcinoma. This disease, short named ACC, is so rare that even its annual incidence couldn’t be accurately calculated (a rough estimate is 1 of a million people). Because of its rarity, few progresses have been made therapeutically. The only FDA approved a drug for ACC is mitotane, an adrenal gland toxin (originally a pesticide). Since 2013, I worked with a group of disease experts (particularly close with Tom Giordano and Gary Hammer from Univ Michigan), to dissect the molecular events and tumor heterogeneity of ACC (Zheng et al. Cancer Cell, 2016). Highlights of our findings include a new driver gene ZNRF3, a genomic event (whole-genome doubling) commonly seen in ACC, telomere abnormalities during disease progression, and three consensus subtypes with distinct prognosis and genetics. This work has inspired efforts to develop assays to customize patient treatment plans.
Example 3: telomeres and telomerase. Most cells of our body are not immortal – they will stop proliferating once reaching a certain number of divisions (Hayflick limit). This is an intrinsic check mechanism preventing cancer development. What enables this check are telomeres and telomerase. The former is a repetitive segment of the hexamer TTAGGG and erodes with every cell division. The latter, silent in somatic cells, is an enzyme that can add new TTAGGG to telomeres to either maintain or elongate it. Very short telomeres trigger senescence and crisis, as happened in most cells. However, cancer cells evade this fate by reactivating telomerase through an expression of its coding gene TERT. Since 2015, we were intrigued by this telomere/telomerase tug-of-war, and designed a systematic study to measure telomere lengths, and enumerated what may help cancer cells regain TERT expression (Barthel et al. Nat Genet, 2017). The most important insight from this study was that promoter methylation might complement mutation in a tissue-dependent manner in reactivating TERT transcription.
Other work. Over the years, we developed numerous tools that have received community attention. Before 2011, I developed network-based tools, including dmGWAS and GenRev. At MD Anderson, I helped develop the fusion calling tool PRADA and TCGA fusion portal. I was also involved in many collaborations. Our most recent work evaluated panel sequencing in the clinical management of glioma, (Zheng, Mol Cancer Ther, 2019).
Where are we headed
Despite our broad interest in understanding the cancer genome, we pay special attention to telomeres and telomerase and are continuing our exploration of their roles in cancer. They are not the only key to cancer cell immortality, but also are intricately linked to genomic instability, most notably aneuploidy. How is telomerase activity regulated? Given its exclusive activity in cancer cells, why has its inhibition not shown satisfactory clinical response? The idea of targeting telomerase remains valid; perhaps it is our targeting strategy that should take the blame. Rather than directly targeting telomerase, can we identify indirect approaches that can overcome our limitations? From a computational perspective, it is imperative to develop methods that can accurately predict telomerase activity; the first step to unsupervised search for novel telomerase regulatory mechanisms that would enable indirect targeting. If we can successfully develop such a method, it would allow us to characterize telomerase activity in tissue development and cancer, and find molecular correlates that will provide new insights into the regulation of this critical complex.
We are also developing new tools that can help our bench colleagues tackle pediatric cancer. Cancers in children pose a unique challenge. They are usually more amenable to treatments but are unmistakably lethal once first-line treatment fails. Further, children are often subject to long term side effects. One initiative we are undertaking is developing a gene expression data based portal. This portal will enable users to navigate multi-modal molecular data and associate them with gene expression. This design is tailored for pediatric cancer because they present much lower genetic alterations (mutation and copy number change) than those in adults. We are working closely with our colleagues to build a tool not only useful to our institute but also the whole research community.
Debodipta Das, PhD
Qilin Li, PhD
Yingli Lyu, PhD
Nighat Noureen, PhD