Interview with Dr. Shiv Singh
Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, UMG
What is your research focus and what are your major research questions?
We are interested in studying how cell-intrinsic transcriptional machineries shape the immunosuppressive tumor microenvironment in pancreatic cancer (PDAC). Our second major research questions is how tumor-extrinsic cytokines/chemokines modulate PDAC.
Recent clinical studies suggest that differential chromatin accessibility and lineage gene programs determine disease prognosis and therapy response in PDAC patients. Our laboratory is focused on identifying tumor subtype-specific transcription factors and epigenetic regulators (i.e. transcriptional machineries) causing heterogeneity and therapeutic vulnerabilities in PDAC, for instance how (epi)-genomic and transcription factors shape cellular identity and impact local tumor microenvironment. These ongoing studies in our laboratory could help us in understanding disease specific role of these transcription machineries at various preclinical stages and for effective therapeutic interventions.
What are findings you are excited about?
Our most recent studies have revealed how a subtype-specific transcriptional program alters disease prognosis and therapy response in PDAC. We strongly believe that changes in tumor-intrinsic transcription machineries govern PDAC plasticity, aggressiveness, and therapy resistance. We propose that identification of the subtype-specific lineage transcription factors and chromatin regulators will predict prognosis and therapy response. We also think that targeting these subtype-specific transcription machineries offers promising novel therapeutic strategies towards stratification-based precision medicine in PDAC and other solids cancers.
What kind of techniques and methods do you use for your research?
Our lab integrates both basic molecular tools and translational/clinical platforms to interrogate complex tumor heterogeneity and therapeutic vulnerabilities in PDAC. All ongoing projects in our laboratory encompass integration of (epi)-genomics and transcriptomic both in tumor cells and in stromal immune compartments. We now have tools to analyze cell-compartment specific transcriptional profiling, which can distinguish human transcriptome from host murine cells in orthotopic tumor models. Using compartment specific transcriptional profiling, we are hoping to uncover neoplastic and stromal-immune gene programs, critical for tumor subtype identity and disease aggressiveness. In addition, our lab has developed a variety of preclinical mouse models such as immunocompetent ‘syngeneic’, immunocompromised, patient-derived xenografts and conditional genetically engineered mouse model.
How can patients benefit from your research?
Our major research questions revolve around how cell-intrinsic/extrinsic factors can change the clinical outcome of PDAC patients. Identifying and characterizing tumor-specific transcriptional mechanisms will not only lead to a better understanding of subtype-specific precision biology, but will also enable tailored therapies for PDAC patients.
What is the biggest challenge in cancer research?
The complex molecular heterogeneity in tumor and stromal immune compartments is the biggest biomedical challenge. It resists conventional therapies and contributes to the dismal prognosis and thus limits the PDAC patient stratification based therapy. Thus, there is an urgent need for advancing molecular screening-based individualized stratification that may help improve overall PDAC patient outcomes.
Selection of Publications
Mechanisms of PDAC subtype heterogeneity and therapy response.
Espinet E, Klein L, Puré E, Singh SK.Trends Cancer. 2022 Dec;8(12):1060-1071. doi: 10.1016/j.trecan.2022.08.005. Epub 2022 Sep 15.
The review was featured on the cover of December 2022 issue of Trends in Cancer.
Axon guidance receptor ROBO3 modulates subtype identity and prognosis via AXL-associated inflammatory network in pancreatic cancer.
Krebs N, Klein L, Wegwitz F, Espinet E, Maurer HC, Tu M, Penz F, Küffer S, Xu X, Bohnenberger H, Cameron S, Brunner M, Neesse A, Kishore U, Hessmann E, Trumpp A, Ströbel P, Brekken RA, Ellenrieder V, Singh SK.JCI Insight. 2022 Aug 22;7(16):e154475. doi: 10.1172/jci.insight.154475.
The paper received very important publication (GöVIP) award in December 2022.
TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer.
Tu M, Klein L, Espinet E, Georgomanolis T, Wegwitz F, Li X, Urbach L, Danieli-Mackay A, Küffer S, Bojarczuk K, Mizi A, Günesdogan U, Chapuy B, Gu Z, Neesse A, Kishore U, Ströbel P, Hessmann E, Hahn SA, Trumpp A, Papantonis A, Ellenrieder V, Singh SK.Nat Cancer. 2021 Nov;2(11):1185-1203. doi: 10.1038/s43018-021-00258-w. Epub 2021 Nov 15.
The paper was featured on the cover page of December 2021 issue of Nature Cancer.
The paper was selected for the preview in Cancer Discovery Journal (BRD4–cJUN–CCL2–TNFα A Maintains Basal-Like Pancreatic Cancer Subtype Identity; DOI: 10.1158/2159-8290.CD-RW2021-171)