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David T. Ting, MDAssistant Physician Mass General Cancer Center Assistant Professor in Medicine Harvard Medical School
Pancreatic and liver 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. Recently, a significant amount of “non-coding” repeat RNAs have been found to be produced in high amounts at the earliest stages of cancer development, but not in normal tissues. Interestingly, these satellite RNAs appear to activate a viral response program that appears to help cancers prevent immune cells from attacking them. The Ting Laboratory has been utilizing innovative microfluidic chip technologies to capture circulating tumor cells (CTCs) and have used satellite RNAs to develop novel blood based early detection biomarkers of cancer. In addition, we are uncovering how these repeat RNAs alter the immune response as a novel immunotherapy target.
David T. Ting, MDPrincipal Investigator
The Ting Laboratory has utilized RNA-sequencing technology to understand the complex transcriptional landscape of cancers. We have used this technology to identify non-coding repeat that are differentially expressed in cancer versus normal tissues. This has provided novel insight into the pathogenesis of PDAC and offers a method to identify novel biomarkers and therapeutic targets. In addition, we have been able to capture pancreatic circulating tumor cells (CTCs) with an innovative microfluidic chip technology and successfully applied RNA-sequencing to these cells to understand their role in the metastatic cascade.
Satellite Non-coding RNAs
RNA sequencing of a broad spectrum of carcinomas demonstrated a highly aberrant expression of non-coding satellite RNAs emanating from pericentromeric heterochromatic regions of the genome previously thought to be inactive due to heavy epigenetic silencing. Analysis of all human satellites identified the HSATII satellite as being exquisitely specific for epithelial cancers including carcinomas of the pancreas, colon, liver, breast, and lung. HSATII expression was confirmed by RNA in situ hybridization (RNA-ISH) and was present in preneoplastic lesions in mouse models and human specimens of the pancreas and colon suggesting satellite expression occurs early in tumorigenesis, which provides for a potential biomarker for early detection and a novel therapeutic avenue. Recently, we have discovered that HSATII is reverse transcribed in cancer cells and can integrate back into the genome and expand these pericentromeric regions. These expansions were found to be a poor prognostic marker in cancer. Moreover, work with others has found that these satellite repeats can affect the local tumor microenvironment with implications for immunotherapies. We are now trying to identify the HSATII reverse transcriptase and better understand the biological role of satellites in cancer progression.
Pancreatic and Liver Circulating Tumor Cells
The temporal development of circulating tumor cells (CTCs) in tumorigenesis is not well understood, but evidence for CTC shedding in early localized cancers suggests that these cells are heterogeneous and that only a small subset of CTCs have the biological potential to metastasize. Using a novel microfluidic device developed at the MGH, we have isolated pancreatic and liver CTCs and perform RNA sequencing on these rare cells. This has revealed the opportunity to develop a novel early detection blood based biomarker and study the metastatic cascade. Using single cell RNA-sequencing, we have characterized the heterogeneity of pancreatic CTCs into three major subclasses, and note that over half of the CTCs are not viable. This illustrates that not all CTCs have the full capacity to metastasize, and that there are likely multiple paths for cancer cell dissemination. In addition, single cell RNA-seq has provided unprecedented transcriptional resolution of CTCs that has revealed significant enrichment for stem cell and epithelial mesenchymal transition markers of these metastatic precursors. Notably, we have also found that CTCs express a significant amount of extracellular matrix proteins normally found in the stroma of primary tumors. This suggests that the seeds of metastasis are in fact producing their own soil during the metastatic cascade. We are currently translating our findings from mouse models to a clinical trial of patients with early pancreatic cancer. The early emergence of CTCs and the opportunity to understand the biology of metastasis in transit offers the potential for developing non-invasive, early detection tools and new strategies to target metastasis.
View a list of publications by researchers at the Ting Laboratory
Desai N*, Sajed D*, Arora KS*, Solovyov A*, Rajurkar M, Bledsoe JR, Sil S, Amri R, Tai E, MacKenzie OC, Mino-Kenudson M, Aryee MJ, Ferrone CR, Berger DL, Rivera MN, Greenbaum BD#, Deshpande V#, Ting DT#. Diverse Repetitive Element RNA Expression Define Epigenetic and Immunologic Features of Colon Cancer. JCI Insight, (2017); 2(3):e91078.
Bersani F, Lee E, Kharchenko PV, Xu AW, Liu M, Xega K, MacKenzie OC, Brannigan BW, Wittner BS, Jung H, Ramaswamy S, Park PJ, Maheswaran S, Ting DT # , and Haber DA #. Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer. Proc Natl Acad Sci U S A, (2015); 112(49): 15148-53.
Tanne A, Muniz LR, Puzio-Kuter A, Leonova KI, Gudkov AV, Ting DT, Monasson R, Cocco S, Levine AJ, Bhardwaj N, and Greenbaum BD. Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells. Proc Natl Acad Sci U S A, (2015); 112(49): 15154-9.
Ting DT, Wittner BS, Ligorio M, Vincent Jordan N, Shah AM, Miya-moto DT, Aceto N, Bersani F, Bran-nigan BW, Xega K, Ciciliano JC, Zhu H, MacKenzie OC, Trautwein J, Arora KS, Shahid M, Ellis HL, Qu N, Bardeesy N, Rivera MN, Deshpande V, Ferrone CR, Kapur R, Ramaswamy S, Shioda T, Toner M, Maheswaran S, Haber DA. Single Cell RNA-sequencing Identiﬁes Extracellular Matrix Gene Expression by Pancreatic Circulating Tumor Cells. Cell Reports, (2014); 8(6): 1905-18.
Yu M*, Ting DT*, Stott SL, Wittner BS, Ozsolak F, Paul S, Ciciliano JC, Smas ME, Winokur D, Gilman AJ, Ulman MJ, Xega K, Contino G, Alagesan B, Brannigan BW, Milos PM, Ryan DP, Sequist LV, Bardeesy N, Ramaswamy S, Toner M, Maheswaran S, Haber DA. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature (2012); 487(7408): 510-3.
Ting DT*, Lipson D*, Paul S, Bran-nigan BW, Akhavanfard S, Coffman EJ, Contino G, Deshpande V, Iafrate AJ, Letosky S, Rivera MN, Bardeesy N, Maheswaran S, Haber DA. Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers. Science (2011); 331(6017): 593-596.
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