Precision Oncology Laboratory: “giving the right drugs, to the right patient, at the right time”
Overall goal of the DasGupta lab is to implement the next-generation functional genomic technologies on individualised patient-derived models to query novel genetic and therapeutic vulnerabilities in solid cancers. The major research focus is to establish novel 'Precision Oncology' platforms (such as patient-derived tumor organoids and primary cancer cell lines) that can be used to: a) study the impact of tumor heterogeneity on the evolutionary mechanisms of tumour metastasis and treatment-resistance; b) identify novel transcriptomic/epigenetic biomarkers of treatment response and tumor progression; c) identify novel therapeutic targets and drug candidates for the precision targeting of specific oncogenic pathways and immune-modulatory response; d) dissect the function of the tumor microenvironment in modulating response to chemo/targeted therapies and immune-oncology drugs.
The DasGupta lab uses a variety of genomic tools to address these questions, including single cell and bulk-transcriptomics, epigenomics, and functional/chemical genomic tools, such as high-throughput/high-content screening (HTS/HCS) technologies.
Additionally, the DasGupta lab is also interested in the identification and functional characterization of non-coding RNAs (ncRNAs), especially lncRNAs and tRNA-derived small RNAs (tsRNAs) in the control of cancer stem cells, oncogenic pathways and embryonic stem cell biology.
RESEARCH PROJECTS in the DGLAB,
1. PRECISION ONCOLOGY
Major focus in the DasGupta lab is to investigate the role of intra-tumor heterogeneity (ITH) and cancer stem cells (CSCs) in tumor metastasis and evolution of treatment resistance: We are employing structural and functional genomic approaches to identify drivers of metastasis and chemo-resistance in patient-derived in vitro organoid and in vivo xenograft models of colorectal, oral and breast cancers (Chia, Low et al., Nat Comm., 2017; Tan et al., Nat Med 2017). In parallel, we are uncovering novel therapeutic targets as well as therapeutic/drug combinations that can preferentially target the destruction of resistant or metastatic cancer cells. Using genomic characterization of patient-derived tumor models, we are developing novel prediction algorithms to predict sensitivity to standard-of-care drugs (Chia, Low et al., Nat Comm., 2017; Tan et al., Nat Med 2017). In separate studies, we have focused on identifying therapeutic vulnerabilities in TKI-resistant HSNCC that are wild type for T790M, a common mutation associated with resistance against TKIs. Finally, we are collaborating with Dr. Hao Fan’s lab at the BII to identify novel small molecule inhibitors of Wnt-b-catenin signaling using in silico screening and in vitro/in vivo validation assays (Low et al., 2018, manuscript in preparation).
2. SINGLE CELL TRANSCRIPTOMICS
We are using single cell genomic technologies to characterise the function/impact of intra-tumor heterogeneity in tumor progression towards metastatic and treatment resistant disease. We do so by employing single cell RNA-seq to map the trajectories of individual cells as they evolve under the selection pressure of drugs and/or metastasis, and investigate the role of clonal/Darwinian selection, epigenetic plasticity and adaptation in tumor progression (Sharma et al., 2018 manuscript in preparation). Additionally we are exploring the function of epigenetic regulation in modulation of specific gene signatures to identify upstream drivers of metastatic and resistant phenotypes. We have also initiated single cell RNA-seq to understand ITH in HCC and breast cancers in order to identify how the tumor microenvironment (TME), including the immune/stromal environment, changes upon treatment with cancer drugs. Additionally we are building capacity for single cell ATAC-seq to investigate epigenetic heterogeneity and plasticity during tumor evolution under selection pressure of drugs and/or metastasis.
3. Non-coding RNAs in STEM CELL and WNT BIOLOGY
The second major focus in the lab is the identification and characterization of novel miRNAs, lncRNAs and small non-coding RNAs that inhibit Wnt/ß-catenin-responsive transcription (CRT), as well as modulate activity of known oncogenic signaling pathways (Saj et al Stem Cells, 2017): Additionally, at the GIS, we are characterizing the function of several novel small RNAs that are differentially expressed/regulated in stem versus differentiating ES cells, as well as in cancer stem cells (CSCs) (Krishna, Yim et al., under review 2018). In the near future we will expand this program into cancer cells in collaboration with Dr. Wan Yue’s lab (GIS) by investigating the function of tsRNA-interactome in regulating cell states.
4. PROTEIN ENGINEERING
The DasGupta lab is also developing novel tools and technologies to generate monobody-based biosensors against treatment-resistant cancer stem cells, and metastasis-initiating cells developed from the patient-derived models generated in the lab. We have already generated a library of binders against key oncogenic proteins such as ß-catenin (Sci Rep., 2013) and Notch-1 (Gocha et al., Scientific Reports., 2017). We are expanding the scaffold-based screen to identify and target the activity of immune cells in the tumor microenvironment that can be used to modulate response to immunotherapy.
- Gocha T, Rao BM, DasGupta R "Identification and characterization of a novel Sso7d scaffold-based binder against Notch1." Sci Rep 2017 Sep 20 ; 7(1) : 12021 Abstract
- Tan DSW, Chong FT, Leong HS, Toh SY, Lau DP, Kwang XL, Zhang X, Sundaram GM, Tan GS, Chang MM, Chua BT, Lim WT, Tan EH, Ang MK, Lim TKH, Sampath P, Chowbay B, Skanderup AJ, DasGupta R, Iyer NG "Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma." Nat Med 2017 Oct ; 23(10) : 1167-1175 Abstract
- Chia S, Low JL, Zhang X, Kwang XL, Chong FT, Sharma A, Bertrand D, Toh SY, Leong HS, Thangavelu MT, Hw ang JSG, Lim KH, Skanthakumar T, Tan HK, Su Y, Hui Choo S, Hentze H, Tan IBH, Lezhava A, Tan P, Tan DSW, Periyasamy G, Koh JLY, Gopalakrishna Iyer N, DasGupta R "Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time." Nat Commun 2017 09 05 ; 8(1) : 435 Abstract
- Saj A, Chatterjee SS, Zhu B, Cukuroglu E, Gocha T, Zhang X, Göke J, DasGupta R "Disrupting Interactions Between β-Catenin and Activating TCFs Reconstitutes Ground State Pluripotency in Mouse Embryonic Stem Cells." Stem Cells 2017 08 ; 35(8) : 1924-1933 Abstract
- Murphy M, Chatterjee SS, Jain S, Katari M, Das Gupta R "TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3." Sci Rep 2016 06 23 ; 6 : 28299 Abstract
- Chatterjee SS, Saj A, Gocha T, Murphy M, Gonsalves FC, Zhang X, Hayward P, Akgöl Oksuz B, Shen SS, Madar A, Martinez Arias A, DasGupta R "Inhibition of β-catenin-TCF1 interaction delays differentiation of mouse embryonic stem cells." J Cell Biol 2015 Oct 12 ; 211(1) : 39-51 Abstract
- Lee E, Madar A, David G, Garabedian MJ, Dasgupta R, Logan SK "Inhibition of androgen receptor and β-catenin activity in prostate cancer." Proc Natl Acad Sci U S A 2013 Sep 24 ; 110(39) : 15710-5 Epub 2013 Sep 9 Abstract
- Narayanan BA, Doudican NA, Park J, Xu D, Narayanan NK, Dasgupta R, Mazumder A "Antagonistic effect of small-molecule inhibitors of Wnt/β-catenin in multiple myeloma." Anticancer Res 2012 Nov ; 32(11) : 4697-707 Abstract
- Gonsalves FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S, Nagourney R, Cardozo T, Brown AM, DasGupta R "An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway." Proc Natl Acad Sci U S A 2011 Apr 12 ; 108(15) : 5954-63 Epub 2011 Mar 10 Abstract
- DasGupta R, Kaykas A, Moon RT, Perrimon N "Functional genomic analysis of the Wnt-wingless signaling pathway." Science 2005 May 6 ; 308(5723) : 826-33 Epub 2005 Apr 7 Abstract