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Research at Mass General
David T. Ting, MDAssistant Physician Mass General Cancer Center Assistant Professor in Medicine Harvard Medical School
Pancreatic cancer remains one of the most deadly 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. RNA sequencing technologies have recently provided unprecedented resolution of how cancer cells behave. Recent analysis of pancreatic tumors has found a signiﬁcant amount of “non-coding” RNAs being produced in cancer cells, but not in normal tissues that have provided new insight into this disease and has implications as novel early detection biomarkers. In addition, the Ting Laboratory has been utilizing innovative microﬂuidic chip technologies to capture circulating tumor cells (CTCs) in the blood of pancreatic cancer patients as a means to understand why pancreatic cancers spread so quickly and as a potential non-invasive tool to diagnose our patients earlier.
David T. Ting, MDPrincipal Investigator
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5% overall survival at 5 years, and therefore, new strategies for early detection and therapeutics are greatly needed. The Ting Laboratory has utilized RNA-sequencing technology to understand the complex transcriptional landscape of PDAC. We have used this technology to identify non-coding sequences (ncRNA) 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 primary PDAC tumors and a variety of normal tissues demonstrated that approximately half of all PDAC transcripts sequenced were unannotated, while nearly all reads in normal pancreas could be aligned, offering a unique opportunity for novel biomarker discovery in PDAC. Initial analysis of this data identiﬁed signiﬁcant transcription emanating from pericentromeric heterochromatic regions of the genome previously thought to be inactive due to heavy epigenetic silencing. Pericentromeric heterochromatin is comprised of large tandem arrays of repetitive elements called satellites and these regions are known to be differentially methylated in a variety of malignancies. Analysis of all human satellites identiﬁed the HSATII satellite as being exquisitely speciﬁc for pancreatic cancer compared to normal pancreatic tissue. HSATII expression was conﬁrmed by RNA in situ hybridization (RNA-ISH) and was present in preneoplastic pancreatic intraepithelial neoplasia (PanIN) suggesting satellite expression occurs early in tumorigenesis, which provides for a potential biomarker for early detection. Furthermore, satellite expression correlated with the expression of a set of genes enriched in stem cells suggests a link between satellites and altered cancer cell fate. 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 have 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 Circulating Tumor Cells
CTCs are cells that have entered the vasculature and are thought to harbor the precursors of metastasis. Using a novel microﬂuidic device developed at the MGH, we have been able to isolate pancreatic CTCs and perform RNA sequencing on these rare cells. RNA-sequencing of these pancreatic CTCs has identiﬁed aberrant WNT signaling as an important pathway in the metastatic process. In particular, the TAK1 kinase was found to be a key part of WNT signaling in CTCs and confers the ability to resist anoikis. The temporal development of 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. We have now developed methods for RNA-sequencing at single cell resolution that has revealed signiﬁcant heterogeneity of pancreatic CTCs. Notably, we ﬁnd 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
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, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brach-tel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S. Circulating breast tumor cells exhibit dynamic changes in epithelial and mes enchymal composition. Science (2013); 339(6119): 580-4.
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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