Krantz Family Center for Cancer Research
2024 Quantum Award: Boosting immunotherapy response while eradicating toxicity
Team: Lloyd Bod, PhD, William L. Hwang, MD, PhD, David T. Ting, MD, and Alexandra-Chloe Villani, PhD.
Learn about the team's project and the Krantz Awards
Gastrointestinal cancers are highly lethal cancers where the vast majority of patients are diagnosed too late and conventional therapies have largely been ineffective, making early detection and novel drug targets greatly needed. The Ting laboratory has been utilizing innovative technologies to characterize RNA expression patterns in cancer. Our lab has identified aberrant expression of repeat RNA in cancer, which have been found to mimic viruses. We have demonstrated that these viral-like repeat sequences can stimulate innate immune responses, replicate through reverse transcriptional intermediates, and infect cells through extracellular vesicles. We have demonstrated found that these repeat RNAs can serve as biomarkers of immunological response, identified therapeutic targets that can disrupt repeat element biology, and visualized the spatial distribution of these viral-like species in tumors and the surrounding microenvironment using spatial transcriptomics. These studies are providing new mechanistic insight into the contribution of repeat elements in cancer progression, identifying novel biomarkers, and discovering new repeat targeting agents.
The Ting laboratory has utilized RNA-sequencing, RNA in situ hybridization, and spatial transcriptomic technologies to understand the complex transcriptional landscape of cancers. We have used these technologies to characterize non-coding repeat RNA expression across cancer and normal tissues. This has provided novel insight into the role of the repeatome in cancer development and offers a method to identify novel biomarkers and therapeutic targets. In addition, we have used single cell, spatial transcriptomic, and microfluidic technologies that have revealed the importance of repeatome biology in driving cellular plasticity and tumor cell heterogeneity. Genetic and molecular disruption of repeat element function can activate innate immune signaling that has been shown to affect tumor growth and block epithelial mesenchymal transition (EMT) plasticity, a cell fate change important for metastasis.
RNA sequencing of a broad spectrum of carcinomas demonstrated a highly aberrant expression of repeat RNAs emanating from regions of the genome previously thought to be inactive due to epigenetic silencing. Our initial work identified the HSATII satellite as being exquisitely specific for epithelial cancers, including carcinomas of the pancreas, colon, liver, breast, and lung. This initial work identified a correlation of satellite expression with neuroendocrine differentiation, a type of cellular plasticity related to EMT and known to occur in the setting of therapy resistance. Furthermore, our work using a microfluidic device to isolate rare circulating tumor cells (CTCs) and single cell RNA-seq revealed high enrichment of repeat element expression in these precursors of metastasis. We have recently demonstrated that repeat RNA expression in cancer cells can induce EMT cellular plasticity through activation of an interferon response, which supports a functional effect of repeat elements on metastatic potential. Using customized probes for repeat RNAs, we have now visualized the spatial localization of repeat RNAs in human cancers using spatial transcriptomics (see f igure), which has shown high levels in tumor cells that are undergoing EMT. Moreover, spatial transcriptomic analysis has revealed presence of repeat RNAs in multiple cells types in the diverse tumor microenvironment ecosystem including cancer associated f ibroblasts (CAFs), neurons, and immune cells. We have demonstrated that repeat RNAs can be delivered to other cell types through extracellular vesicles (EVs) that mimic viral particles, which induce innate immune responses that alter the phenotype of different cell types. Altogether, this represents a model of a cancer driven inflammatory response in the tumor microenvironment through an “infection” of repeat RNA containing EVs.
Different repeat elements have been shown to replicate through reverse transcriptional intermediates, including human endogenous retroviruses (HERVs), the LINE-1 retrotransposon, and satellite repeats. These insertions and expansions in the genome have been found to be a poor prognostic marker in cancer. In preclinical tumor models, we showed the ability to inhibit replication of repeat elements using nucleoside reverse transcriptase inhibitors (NRTIs), drugs commonly used for viral infection. This led to a Phase II clinical trial of the NRTI 3TC in metastatic colorectal cancer, which demonstrated promising single agent activity in 25% of patients. Preclinical models indicate that NRTIs affect migratory capability and clonal growth, which supports a role of retrotransposon activity. We are expanding our studies on the impact of NRTIs on cancer cells and the surrounding microenvironment. Recently, we have focused on the RNA binding protein component of the LINE-1 retrotransposon called ORF1p. Suppression of ORF1p with shRNA had significant effects on tumorsphere and xenograft growth, which was linked with alterations in interferon response and diminished EMT. Altogether, these findings have opened new therapeutic avenues to target repeatome biology.
The Ting Laboratory at the Mass General Cancer Center and Harvard Medical School is looking for post-doctoral researchers interested in translational research projects in gastrointestinal malignancies including pancreatic, colorectal cancer, and liver cancer.
There are two major projects being pursued by the laboratory.
The first is the study of a novel class of non-coding RNAs called satellites, which were found to be highly and specifically expressed in cancers compared to normal tissues (Ting DT*, Lipson D*, et al. Science 2011; Bersani et al. PNAS 2015; Desai et al. JCI Insight 2017; Solovyov et al. Cell Reports 2018). This work has implications as a clinical cancer biomarker, as well as an interesting area of research to elucidate the role of these repeat RNAs in cancer biology. We are looking for a biologist interested in studying the biology of these repeats in cancer and their impact on the tumor immune microenvironment.
The second is the study of the role of single cell heterogeneity on metastasis and resistance to chemotherapy. Our lab utilizes innovative circulating tumor cell (CTC) isolation technology to study the features that define these metastatic precursors (Yu M*, Ting DT*, et al. Nature 2012; Ting DT et al. Cell Reports 2014; Franses J et al. Oncologist 2017; Bhan I et al. Gastroenterology 2018). Recent work using single cell RNA-seq and other single cell spatial profiling has shown the importance of the tumor microenvironment in driving single cell heterogeneity in pancreatic cancer (Ligorio M et al. Cell 2019) and the functional importance of cancer cell plasticity in response to chemotherapy (Porter RL et al. PNAS 2019). We are looking for a biologist interested in further understanding the factors important in driving single cell phenotypes and developing new therapeutic targets.
The laboratory is currently composed of 1 hepatologist junior faculty, 2 oncology junior faculty, 6 postdoctoral researchers, 1 computational staff scientist, 1 microscopy staff scientist, and 6 research technicians. Our multidisciplinary team will provide a rich environment to do cutting edge translational biology research.
If you are interested in this position, please email David T. Ting, MD at dting1@mgh.harvard.edu with your CV and a brief description of your goals from this research experience.
PDF of Postdoctoral Research Position Listing
View a list of publications by researchers at the Ting Laboratory
Selected Publications
Taylor MS, Wu C, Fridy PC, Zhang SJ, Senussi Y, Wolters JC, Cajuso T, Cheng WC, […], Ting DT, Rout MP, LaCava J, Walt DR, and Burns KH, Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker. Cancer Discov, (2023); 13(12): 25322547
Porter RL*, Sun S*, Flores MN, Berzolla E, You E, Phillips IE, Kc N, Desai N, [...] Stott SL, Deshpande V, Liu JF, Solovyov A, Matulonis UA, Greenbaum BD†, and Ting DT†. Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype. J Clin Invest, 2022 Aug 15;132(16):e155931.
Rajurkar M*, Parikh AR*, Solovyov A*, You E, Kulkarni AS, Chu C, Xu KH, Jaicks C, Taylor MS, Wu C, Alexander KA, Good CR, Szabolcs A, Gerstberger S, [...] Deshpande V, Rivera MN, Aryee MJ, Hong TS, Berger SL, Walt DR, Burns KH, Park PJ, Greenbaum BD†, and Ting DT†. Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer Discovery, (2022).
Parikh AR*, Szabolcs A*, Allen JN, Clark JW, Wo JY, Raabe M, Thel H, Hoyos D, Mehta A, [...] Greenbaum BD, Ting DT†, and Hong TS†. Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Nat Cancer, (2021); 2(11): 1124-1135.
Franses JW*, Philipp J*, Missios P, Bhan I, Liu A, Yashaswini C, Tai E, [...] Ryan DP, Maheswaran S, Haber DA, Daley GQ, and Ting DT. Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target. Nature Communications (2020); 11(1): 3303.
Ligorio M*, Sil S*, Malagnon-Lopez J, Nieman LT, [...] Fernandez-Del Castillo C, Ferrone CR, Haas W, Aryee M†, Ting DT†. Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. Cell (2019); 178(1):160-175.e27. .
*Equal contribution
†Co-corresponding
This image represents a spatial transcriptomic “map” of a pancreatic cancer with individual molecules of repeat and coding RNAs quantified with precise spatial coordinates in a human primary tumor sample. Individual cell types can be determined based on transcriptional profiles with mapping to understand cell-cell interactions within tissue.
Principal Investigator
