SpringerLink
Log in

Transcriptomic Analysis of CTCs

  • Chapter
  • First Online:
Circulating Tumor Cells

Part of the book series: Current Cancer Research ((CUCR))

  • 398 Accesses

Abstract

Circulating tumor cells (CTCs), the “seeds” of fatal metastasis, intravasate into the bloodstream throughout the early stages of cancer, promoting the generation of micrometastatic reservoirs, some of which ultimately evolve to metastatic tumors. Though CTC enumeration has been invaluable in prognosticating metastatic cancer progression and response to treatment, therapeutic targeting of CTCs remains a future objective because signaling mechanisms of CTCs are largely unknown. In this chapter, we describe methods of CTC isolation, their cell surface antigenic and mutational signature validation, and CTCs’ comprehensive transcriptomic characterization.

First, we highlight these concepts and unique CTC gene expression signatures by transcriptomic analyses, showing that CTCs harbor a significant proportion of mitotically inactive cells. Conversely, CTCs associated with breast cancer brain metastasis (BCBM) possess increased Notch signaling and immune-evasion pathways. Second, we generated an in vivo model of clinical metastatic dormancy by the systemic injection of CTC-enriched cell populations in immunodeficient mice (NSG), which revealed that mTOR signaling maintains dormancy in bone marrow-resident breast cancer cells (BMRTCs). Third, we developed a model of liver metastasis using sequential grafting of CTCs derived from triple-negative breast cancer patients and identified integrin signaling as a major pathway in liver metastasis. Lastly, by employing similar strategies in melanoma patient-derived CTCs and transcriptional profiling, we have reported that selective targeting of the USP7 pathway reduces micrometastatic burden in preclinical models. Collectively, these studies demonstrate the feasibility and reproducibility of undertaking CTC transcriptomic analyses. We foresee that the advent of single-cell sequencing/feature barcoding technologies will usher a new area and foster important discoveries in CTC transcriptomics to address unmet clinical needs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (Canada)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (Canada)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hüsemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmüller G, Klein CA (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13 (1):58-68. doi:https://doi.org/10.1016/j.ccr.2007.12.003

    Article  CAS  PubMed  Google Scholar 

  2. Hosseini H, Obradović MMS, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M, Nanduri LK, Werno C, Ehrl C, Maneck M, Patwary N, Haunschild G, Gužvić M, Reimelt C, Grauvogl M, Eichner N, Weber F, Hartkopf AD, Taran FA, Brucker SY, Fehm T, Rack B, Buchholz S, Spang R, Meister G, Aguirre-Ghiso JA, Klein CA (2016) Early dissemination seeds metastasis in breast cancer. Nature 540 (7634):552-558. doi:https://doi.org/10.1038/nature20785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351 (8):781-791. doi:https://doi.org/10.1056/NEJMoa040766

    Article  CAS  PubMed  Google Scholar 

  4. Alix-Panabières C, Pantel K (2021) Liquid Biopsy: From Discovery to Clinical Application. Cancer Discovery 11 (4):858-873. doi:https://doi.org/10.1158/2159-8290.Cd-20-1311

    Article  PubMed  Google Scholar 

  5. Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, Telli ML, Advani RH, Carlson RW, Mollick JA, Sheth S, Kurian AW, Ford JM, Stockdale FE, Quake SR, Pease RF, Mindrinos MN, Bhanot G, Dairkee SH, Davis RW, Jeffrey SS (2012) Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One 7 (5):e33788. doi:https://doi.org/10.1371/journal.pone.0033788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. D’Avola D, Villacorta-Martin C, Martins-Filho SN, Craig A, Labgaa I, von Felden J, Kimaada A, Bonaccorso A, Tabrizian P, Hartmann BM, Sebra R, Schwartz M, Villanueva A (2018) High-density single cell mRNA sequencing to characterize circulating tumor cells in hepatocellular carcinoma. Scientific Reports 8 (1):11570. doi:https://doi.org/10.1038/s41598-018-30047-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ramsköld D, Luo S, Wang YC, Li R, Deng Q, Faridani OR, Daniels GA, Khrebtukova I, Loring JF, Laurent LC, Schroth GP, Sandberg R (2012) Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. Nat Biotechnol 30 (8):777-782. doi:https://doi.org/10.1038/nbt.2282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 (2012) RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 487 (7408):510-513. doi:https://doi.org/10.1038/nature11217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lang JE, Ring A, Porras T, Kaur P, Forte VA, Mineyev N, Tripathy D, Press MF, Campo D (2018) RNA-Seq of Circulating Tumor Cells in Stage II-III Breast Cancer. Ann Surg Oncol 25 (8):2261-2270. doi:https://doi.org/10.1245/s10434-018-6540-4

    Article  PubMed  PubMed Central  Google Scholar 

  10. Porras TB, Kaur P, Ring A, Schechter N, Lang JE (2018) Challenges in using liquid biopsies for gene expression profiling. Oncotarget 9 (6):7036-7053. doi:https://doi.org/10.18632/oncotarget.24140

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J (2009) Tumor self-seeding by circulating cancer cells. Cell 139 (7):1315-1326. doi:https://doi.org/10.1016/j.cell.2009.11.025

    Article  PubMed  PubMed Central  Google Scholar 

  12. Comen E, Norton L, Massagué J (2011) Clinical implications of cancer self-seeding. Nature Reviews Clinical Oncology 8 (6):369-377. doi:https://doi.org/10.1038/nrclinonc.2011.64

    Article  PubMed  Google Scholar 

  13. Kang Y, Pantel K (2013) Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23 (5):573-581. doi:https://doi.org/10.1016/j.ccr.2013.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu T, Ma Q, Zhang Y, Wang X, Xu K, Yan K, Dong W, Fan Q, Zhang Y, Qiu X (2019) Self-seeding circulating tumor cells promote the proliferation and metastasis of human osteosarcoma by upregulating interleukin-8. Cell Death & Disease 10 (8):575. doi:https://doi.org/10.1038/s41419-019-1795-7

    Article  CAS  Google Scholar 

  15. Zhang Y, Ma Q, Liu T, Guan G, Zhang K, Chen J, Jia N, Yan S, Chen G, Liu S, Jiang K, Lu Y, Wen Y, Zhao H, Zhou Y, Fan Q, Qiu X (2016) Interleukin-6 suppression reduces tumour self-seeding by circulating tumour cells in a human osteosarcoma nude mouse model. Oncotarget 7 (1):446-458. doi:https://doi.org/10.18632/oncotarget.6371

    Article  CAS  PubMed  Google Scholar 

  16. Worrede A, Meucci O, Fatatis A (2019) Limiting tumor seeding as a therapeutic approach for metastatic disease. Pharmacol Ther 199:117-128. doi:https://doi.org/10.1016/j.pharmthera.2019.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ignatiadis M, Sledge GW, Jeffrey SS (2021) Liquid biopsy enters the clinic — implementation issues and future challenges. Nature Reviews Clinical Oncology. doi:https://doi.org/10.1038/s41571-020-00457-x

  18. Li YC, Zou JM, Luo C, Shu Y, Luo J, Qin J, Wang Y, Li D, Wang SS, Chi G, Guo F, Zhang GM, Feng ZH (2017) Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation. Oncotarget 8 (17):28418-28430. doi:https://doi.org/10.18632/oncotarget.16084

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pal A, Shinde R, Miralles MS, Workman P, de Bono J (2021) Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development. Nature Reviews Clinical Oncology. doi:https://doi.org/10.1038/s41571-021-00489-x

  20. Castro-Giner F, Aceto N (2020) Tracking cancer progression: from circulating tumor cells to metastasis. Genome Medicine 12 (1):31. doi:https://doi.org/10.1186/s13073-020-00728-3

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kwan TT, Bardia A, Spring LM, Giobbie-Hurder A, Kalinich M, Dubash T, Sundaresan T, Hong X, LiCausi JA, Ho U, Silva EJ, Wittner BS, Sequist LV, Kapur R, Miyamoto DT, Toner M, Haber DA, Maheswaran S (2018) A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer. Cancer Discov 8 (10):1286-1299. doi:https://doi.org/10.1158/2159-8290.Cd-18-0432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Strati A, Nikolaou M, Georgoulias V, Lianidou ES (2021) RNA-Based CTC Analysis Provides Prognostic Information in Metastatic Breast Cancer. Diagnostics (Basel) 11 (3). doi:https://doi.org/10.3390/diagnostics11030513

  23. Aya-Bonilla C, Gray ES, Manikandan J, Freeman JB, Zaenker P, Reid AL, Khattak MA, Frank MH, Millward M, Ziman M (2019) Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles. Cancers (Basel) 11 (2). doi:https://doi.org/10.3390/cancers11020157

  24. Aya-Bonilla CA, Morici M, Hong X, McEvoy AC, Sullivan RJ, Freeman J, Calapre L, Khattak MA, Meniawy T, Millward M, Ziman M, Gray ES (2020) Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells. Br J Cancer 122 (7):1059-1067. doi:https://doi.org/10.1038/s41416-020-0750-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dasgupta A, Lim AR, Ghajar CM (2017) Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol 11 (1):40-61. doi:https://doi.org/10.1002/1878-0261.12022

    Article  PubMed  PubMed Central  Google Scholar 

  26. Diel IJ, Cote RJ (2000) Bone marrow and lymph node assessment for minimal residual disease in patients with breast cancer. Cancer Treat Rev 26 (1):53-65. doi:https://doi.org/10.1053/ctrv.1999.0150

    Article  CAS  PubMed  Google Scholar 

  27. Nevel KS, Wilcox JA, Robell LJ, Umemura Y (2018) The Utility of Liquid Biopsy in Central Nervous System Malignancies. Curr Oncol Rep 20 (8):60. doi:https://doi.org/10.1007/s11912-018-0706-x

    Article  CAS  PubMed  Google Scholar 

  28. Boire A, Brandsma D, Brastianos PK, Le Rhun E, Ahluwalia M, Junck L, Glantz M, Groves MD, Lee EQ, Lin N, Raizer J, Rudà R, Weller M, Van den Bent MJ, Vogelbaum MA, Chang S, Wen PY, Soffietti R (2019) Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications. Neuro Oncol 21 (5):571-584. doi:https://doi.org/10.1093/neuonc/noz012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, Liu CM, Deangelis LM, Omuro A (2013) Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 80 (17):1598-1605; discussion 1603. doi:https://doi.org/10.1212/WNL.0b013e31828f183f

    Article  PubMed  PubMed Central  Google Scholar 

  30. Milojkovic Kerklaan B, Pluim D, Bol M, Hofland I, Westerga J, van Tinteren H, Beijnen JH, Boogerd W, Schellens JH, Brandsma D (2016) EpCAM-based flow cytometry in cerebrospinal fluid greatly improves diagnostic accuracy of leptomeningeal metastases from epithelial tumors. Neuro Oncol 18 (6):855-862. doi:https://doi.org/10.1093/neuonc/nov273

    Article  CAS  PubMed  Google Scholar 

  31. Magbanua MJ, Melisko M, Roy R, Sosa EV, Hauranieh L, Kablanian A, Eisenbud LE, Ryazantsev A, Au A, Scott JH, Park JW (2013) Molecular profiling of tumor cells in cerebrospinal fluid and matched primary tumors from metastatic breast cancer patients with leptomeningeal carcinomatosis. Cancer Res 73 (23):7134-7143. doi:https://doi.org/10.1158/0008-5472.Can-13-2051

    Article  CAS  PubMed  Google Scholar 

  32. Le Rhun E, Tu Q, De Carvalho Bittencourt M, Farre I, Mortier L, Cai H, Kohler C, Faure GC (2013) Detection and quantification of CSF malignant cells by the CellSearch® technology in patients with melanoma leptomeningeal metastasis. Medical Oncology 30 (2):538. doi:https://doi.org/10.1007/s12032-013-0538-3

    Article  CAS  PubMed  Google Scholar 

  33. Cordone I, Masi S, Summa V, Carosi M, Vidiri A, Fabi A, Pasquale A, Conti L, Rosito I, Carapella CM, Villani V, Pace A (2017) Overexpression of syndecan-1, MUC-1, and putative stem cell markers in breast cancer leptomeningeal metastasis: a cerebrospinal fluid flow cytometry study. Breast Cancer Res 19 (1):46. doi:https://doi.org/10.1186/s13058-017-0827-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li X, Zhang Y, Ding J, Wang M, Li N, Yang H, Wang K, Wang D, Lin PP, Li M, Zhao Z, Liu P (2018) Clinical significance of detecting CSF-derived tumor cells in breast cancer patients with leptomeningeal metastasis. Oncotarget 9 (2):2705-2714. doi:https://doi.org/10.18632/oncotarget.23597

    Article  PubMed  Google Scholar 

  35. Ruan H, Zhou Y, Shen J, Zhai Y, Xu Y, Pi L, Huang R, Chen K, Li X, Ma W, Wu Z, Deng X, Wang X, Zhang C, Guan M (2020) Circulating tumor cell characterization of lung cancer brain metastases in the cerebrospinal fluid through single-cell transcriptome analysis. Clin Transl Med 10 (8):e246. doi:https://doi.org/10.1002/ctm2.246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lin X, Fleisher M, Rosenblum M, Lin O, Boire A, Briggs S, Bensman Y, Hurtado B, Shagabayeva L, DeAngelis LM, Panageas KS, Omuro A, Pentsova EI (2017) Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro-Oncology 19 (9):1248-1254. doi:https://doi.org/10.1093/neuonc/nox066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O’Rourke MA, Lew DL, Doyle GV, Gralow JR, Livingston RB, Hayes DF (2014) Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 32 (31):3483-3489. doi:https://doi.org/10.1200/jco.2014.56.2561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Goldkorn A, Ely B, Quinn DI, Tangen CM, Fink LM, Xu T, Twardowski P, Van Veldhuizen PJ, Agarwal N, Carducci MA, Monk JP, 3rd, Datar RH, Garzotto M, Mack PC, Lara P, Jr., Higano CS, Hussain M, Thompson IM, Jr., Cote RJ, Vogelzang NJ (2014) Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J Clin Oncol 32 (11):1136-1142. doi:https://doi.org/10.1200/jco.2013.51.7417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, Meropol NJ (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26 (19):3213-3221. doi:https://doi.org/10.1200/jco.2007.15.8923

    Article  PubMed  Google Scholar 

  40. Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, Heller G (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 10 (3):233-239. doi:https://doi.org/10.1016/s1470-2045(08)70340-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Larsson A-M, Jansson S, Bendahl P-O, Levin Tykjaer Jörgensen C, Loman N, Graffman C, Lundgren L, Aaltonen K, Rydén L (2018) Longitudinal enumeration and cluster evaluation of circulating tumor cells improve prognostication for patients with newly diagnosed metastatic breast cancer in a prospective observational trial. Breast Cancer Research 20 (1):48. doi:https://doi.org/10.1186/s13058-018-0976-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vishnoi M, Peddibhotla S, Yin W, Scamardo AT, George GC, Hong DS, Marchetti D (2015) The isolation and characterization of CTC subsets related to breast cancer dormancy. Sci Rep 5:17533. doi:https://doi.org/10.1038/srep17533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, Danila DC, Healy P, Anand M, Rothwell CJ, Rasmussen J, Thornburg B, Berry WR, Wilder RS, Lu C, Chen Y, Silberstein JL, Kemeny G, Galletti G, Somarelli JA, Gupta S, Gregory SG, Scher HI, Dittamore R, Tagawa ST, Antonarakis ES, George DJ (2019) Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study. J Clin Oncol 37 (13):1120-1129. doi:https://doi.org/10.1200/jco.18.01731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Scher HI, Graf RP, Schreiber NA, Jayaram A, Winquist E, McLaughlin B, Lu D, Fleisher M, Orr S, Lowes L, Anderson A, Wang Y, Dittamore R, Allan AL, Attard G, Heller G (2018) Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer. JAMA Oncol 4 (9):1179-1186. doi:https://doi.org/10.1001/jamaoncol.2018.1621

    Article  PubMed  PubMed Central  Google Scholar 

  45. Seitz AK, Thoene S, Bietenbeck A, Nawroth R, Tauber R, Thalgott M, Schmid S, Secci R, Retz M, Gschwend JE, Ruland J, Winter C, Heck MM (2017) AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide. Eur Urol 72 (5):828-834. doi:https://doi.org/10.1016/j.eururo.2017.07.024

    Article  CAS  PubMed  Google Scholar 

  46. Cabel L, Proudhon C, Gortais H, Loirat D, Coussy F, Pierga JY, Bidard FC (2017) Circulating tumor cells: clinical validity and utility. Int J Clin Oncol 22 (3):421-430. doi:https://doi.org/10.1007/s10147-017-1105-2

    Article  PubMed  Google Scholar 

  47. 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, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339 (6119):580-584. doi:https://doi.org/10.1126/science.1228522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Markou A, Lazaridou M, Paraskevopoulos P, Chen S, Świerczewska M, Budna J, Kuske A, Gorges TM, Joosse SA, Kroneis T, Zabel M, Sedlmayr P, Alix-Panabières C, Pantel K, Lianidou ES (2018) Multiplex Gene Expression Profiling of In Vivo Isolated Circulating Tumor Cells in High-Risk Prostate Cancer Patients. Clin Chem 64 (2):297-306. doi:https://doi.org/10.1373/clinchem.2017.275503

    Article  CAS  PubMed  Google Scholar 

  49. Boral D, Marchetti D (2018) Liquid Biopsy in Prostate Cancer: A Case for Comprehensive Genomic Characterization of Circulating Tumor Cells. Clin Chem 64 (2):251-253. doi:https://doi.org/10.1373/clinchem.2017.283440

    Article  CAS  PubMed  Google Scholar 

  50. Boral D, Vishnoi M, Liu HN, Yin W, Sprouse ML, Scamardo A, Hong DS, Tan TZ, Thiery JP, Chang JC, Marchetti D (2017) Molecular characterization of breast cancer CTCs associated with brain metastasis. Nat Commun 8 (1):196. doi:https://doi.org/10.1038/s41467-017-00196-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vishnoi M, Liu NH, Yin W, Boral D, Scamardo A, Hong D, Marchetti D (2019) The identification of a TNBC liver metastasis gene signature by sequential CTC-xenograft modeling. Mol Oncol 13 (9):1913-1926. doi:https://doi.org/10.1002/1878-0261.12533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Boral D, Liu HN, Kenney SR, Marchetti D (2020) Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer. Cancers (Basel) 12 (6). doi:https://doi.org/10.3390/cancers12061626

  53. Sprouse ML, Welte T, Boral D, Liu HN, Yin W, Vishnoi M, Goswami-Sewell D, Li L, Pei G, Jia P, Glitza-Oliva IC, Marchetti D (2019) PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling. Int J Mol Sci 20 (8). doi:https://doi.org/10.3390/ijms20081916

  54. Vishnoi M, Boral D, Liu H, Sprouse ML, Yin W, Goswami-Sewell D, Tetzlaff MT, Davies MA, Oliva ICG, Marchetti D (2018) Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow-Resident Melanoma CTCs. Cancer Res 78 (18):5349-5362. doi:https://doi.org/10.1158/0008-5472.Can-18-0644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158 (5):1110-1122. doi:https://doi.org/10.1016/j.cell.2014.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8 (2):98-101

    CAS  PubMed  Google Scholar 

  57. Balakrishnan A, Koppaka D, Anand A, Deb B, Grenci G, Viasnoff V, Thompson EW, Gowda H, Bhat R, Rangarajan A, Thiery JP, Govind Babu K, Kumar P (2019) Circulating Tumor Cell cluster phenotype allows monitoring response to treatment and predicts survival. Scientific Reports 9 (1):7933. doi:https://doi.org/10.1038/s41598-019-44404-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mu Z, Wang C, Ye Z, Austin L, Civan J, Hyslop T, Palazzo JP, Jaslow R, Li B, Myers RE, Jiang J, **ng J, Yang H, Cristofanilli M (2015) Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer. Breast Cancer Res Treat 154 (3):563-571. doi:https://doi.org/10.1007/s10549-015-3636-4

    Article  CAS  PubMed  Google Scholar 

  59. Lu L, Zeng H, Gu X, Ma W (2015) Circulating tumor cell clusters-associated gene plakoglobin and breast cancer survival. Breast Cancer Res Treat 151 (3):491-500. doi:https://doi.org/10.1007/s10549-015-3416-1

    Article  CAS  PubMed  Google Scholar 

  60. Gkountela S, Castro-Giner F, Szczerba BM, Vetter M, Landin J, Scherrer R, Krol I, Scheidmann MC, Beisel C, Stirnimann CU, Kurzeder C, Heinzelmann-Schwarz V, Rochlitz C, Weber WP, Aceto N (2019) Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell 176 (1-2):98-112.e114. doi:https://doi.org/10.1016/j.cell.2018.11.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Giuliano M, Shaikh A, Lo HC, Arpino G, De Placido S, Zhang XH, Cristofanilli M, Schiff R, Trivedi MV (2018) Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize. Cancer Research 78 (4):845-852. doi:https://doi.org/10.1158/0008-5472.Can-17-2748

    Article  CAS  PubMed  Google Scholar 

  62. Szczerba BM, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J, Scheidmann MC, Donato C, Scherrer R, Singer J, Beisel C, Kurzeder C, Heinzelmann-Schwarz V, Rochlitz C, Weber WP, Beerenwinkel N, Aceto N (2019) Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. doi:https://doi.org/10.1038/s41586-019-0915-y

  63. Karreman MA, Winkler F (2018) The mechanics of metastatic seeding. Nat Cell Biol 20 (8):860-862. doi:https://doi.org/10.1038/s41556-018-0162-8

    Article  CAS  PubMed  Google Scholar 

  64. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148 (1-2):349-361. doi:https://doi.org/10.1016/j.cell.2011.11.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rack B, Schindlbeck C, Jückstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann MW, Friese K, Pantel K, Janni W (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 106 (5). doi:https://doi.org/10.1093/jnci/dju066

  66. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, Groom AC (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153 (3):865-873. doi:https://doi.org/10.1016/s0002-9440(10)65628-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Klein CA (2013) Selection and adaptation during metastatic cancer progression. Nature 501 (7467):365-372. doi:https://doi.org/10.1038/nature12628

    Article  CAS  PubMed  Google Scholar 

  68. Pantel K, Alix-Panabières C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6 (6):339-351. doi:https://doi.org/10.1038/nrclinonc.2009.44

    Article  CAS  PubMed  Google Scholar 

  69. Bidard FC, Vincent-Salomon A, Gomme S, Nos C, de Rycke Y, Thiery JP, Sigal-Zafrani B, Mignot L, Sastre-Garau X, Pierga JY (2008) Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 14 (11):3306-3311. doi:https://doi.org/10.1158/1078-0432.Ccr-07-4749

    Article  CAS  PubMed  Google Scholar 

  70. Janni W, Vogl FD, Wiedswang G, Synnestvedt M, Fehm T, Jückstock J, Borgen E, Rack B, Braun S, Sommer H, Solomayer E, Pantel K, Nesland J, Friese K, Naume B (2011) Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse--a European pooled analysis. Clin Cancer Res 17 (9):2967-2976. doi:https://doi.org/10.1158/1078-0432.Ccr-10-2515

    Article  PubMed  Google Scholar 

  71. Zheng H, Kang Y (2015) Cradle of evil: osteogenic niche for early bone metastasis. Cancer Cell 27 (2):153-155. doi:https://doi.org/10.1016/j.ccell.2015.01.006

    Article  CAS  PubMed  Google Scholar 

  72. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, Foekens JA, Massagué J (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16 (1):67-78. doi:https://doi.org/10.1016/j.ccr.2009.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Massagué J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529 (7586):298-306. doi:https://doi.org/10.1038/nature17038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kimball SR (1999) Eukaryotic initiation factor eIF2. Int J Biochem Cell Biol 31 (1):25-29. doi:https://doi.org/10.1016/s1357-2725(98)00128-9

    Article  CAS  PubMed  Google Scholar 

  75. Cheung TH, Rando TA (2013) Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol 14 (6):329-340. doi:https://doi.org/10.1038/nrm3591

    Article  CAS  PubMed  Google Scholar 

  76. Ranganathan AC, Adam AP, Aguirre-Ghiso JA (2006) Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy. Cell Cycle 5 (16):1799-1807. doi:https://doi.org/10.4161/cc.5.16.3109

    Article  CAS  PubMed  Google Scholar 

  77. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14 (14):1296-1302. doi:https://doi.org/10.1016/j.cub.2004.06.054

    Article  CAS  PubMed  Google Scholar 

  78. Mukhopadhyay S, Frias MA, Chatterjee A, Yellen P, Foster DA (2016) The Enigma of Rapamycin Dosage. Mol Cancer Ther 15 (3):347-353. doi:https://doi.org/10.1158/1535-7163.Mct-15-0720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim LC, Cook RS, Chen J (2017) mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene 36 (16):2191-2201. doi:https://doi.org/10.1038/onc.2016.363

    Article  CAS  PubMed  Google Scholar 

  80. Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, Gusenleitner D, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Flaherty K, Larkin J, Robert C, Kefford R, Kirkwood JM, Hauschild A, Schadendorf D, Long GV (2020) Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF(V600)-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol 21 (3):358-372. doi:https://doi.org/10.1016/s1470-2045(20)30062-0

    Article  CAS  PubMed  Google Scholar 

  81. Mohme M, Riethdorf S, Pantel K (2017) Circulating and disseminated tumour cells — mechanisms of immune surveillance and escape. Nature Reviews Clinical Oncology 14 (3):155-167. doi:https://doi.org/10.1038/nrclinonc.2016.144

    Article  CAS  PubMed  Google Scholar 

  82. Leong SP, Tseng WW (2014) Micrometastatic cancer cells in lymph nodes, bone marrow, and blood: Clinical significance and biologic implications. CA Cancer J Clin 64 (3):195-206. doi:https://doi.org/10.3322/caac.21217

    Article  PubMed  Google Scholar 

  83. Vishnoi M, Marchetti D (2018) Targeting melanoma residual disease by USP7. Oncotarget 9 (101):37464-37465. doi:https://doi.org/10.18632/oncotarget.26497

    Article  PubMed  PubMed Central  Google Scholar 

  84. Nininahazwe L, Liu B, He C, Zhang H, Chen ZS (2021) The emerging nature of Ubiquitin-specific protease 7 (USP7): a new target in cancer therapy. Drug Discov Today 26 (2):490-502. doi:https://doi.org/10.1016/j.drudis.2020.10.028

    Article  CAS  PubMed  Google Scholar 

  85. Turnbull AP, Ioannidis S, Krajewski WW, Pinto-Fernandez A, Heride C, Martin ACL, Tonkin LM, Townsend EC, Buker SM, Lancia DR, Caravella JA, Toms AV, Charlton TM, Lahdenranta J, Wilker E, Follows BC, Evans NJ, Stead L, Alli C, Zarayskiy VV, Talbot AC, Buckmelter AJ, Wang M, McKinnon CL, Saab F, McGouran JF, Century H, Gersch M, Pittman MS, Marshall CG, Raynham TM, Simcox M, Stewart LMD, McLoughlin SB, Escobedo JA, Bair KW, Dinsmore CJ, Hammonds TR, Kim S, Urbé S, Clague MJ, Kessler BM, Komander D (2017) Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 550 (7677):481-486. doi:https://doi.org/10.1038/nature24451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhou J, Wang J, Chen C, Yuan H, Wen X, Sun H (2018) USP7: Target Validation and Drug Discovery for Cancer Therapy. Med Chem 14 (1):3-18. doi:https://doi.org/10.2174/1573406413666171020115539

    Article  CAS  PubMed  Google Scholar 

  87. Lo KW, Lo YM, Leung SF, Tsang YS, Chan LY, Johnson PJ, Hjelm NM, Lee JC, Huang DP (1999) Analysis of cell-free Epstein-Barr virus associated RNA in the plasma of patients with nasopharyngeal carcinoma. Clin Chem 45 (8 Pt 1):1292-1294

    Article  CAS  PubMed  Google Scholar 

  88. Alix-Panabières C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14 (9):623-631. doi:https://doi.org/10.1038/nrc3820

    Article  CAS  PubMed  Google Scholar 

  89. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J (2014) AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371 (11):1028-1038. doi:https://doi.org/10.1056/NEJMoa1315815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, Desai R, Fox DB, Brannigan BW, Trautwein J, Arora KS, Desai N, Dahl DM, Sequist LV, Smith MR, Kapur R, Wu C-L, Shioda T, Ramaswamy S, Ting DT, Toner M, Maheswaran S, Haber DA (2015) RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349 (6254):1351-1356. doi:https://doi.org/10.1126/science.aab0917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hong X, Sullivan RJ, Kalinich M, Kwan TT, Giobbie-Hurder A, Pan S, LiCausi JA, Milner JD, Nieman LT, Wittner BS, Ho U, Chen T, Kapur R, Lawrence DP, Flaherty KT, Sequist LV, Ramaswamy S, Miyamoto DT, Lawrence M, Toner M, Isselbacher KJ, Maheswaran S, Haber DA (2018) Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy. Proc Natl Acad Sci U S A 115 (10):2467-2472. doi:https://doi.org/10.1073/pnas.1719264115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jordan NV, Bardia A, Wittner BS, Benes C, Ligorio M, Zheng Y, Yu M, Sundaresan TK, Licausi JA, Desai R, O’Keefe RM, Ebright RY, Boukhali M, Sil S, Onozato ML, Iafrate AJ, Kapur R, Sgroi D, Ting DT, Toner M, Ramaswamy S, Haas W, Maheswaran S, Haber DA (2016) HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature 537 (7618):102-106. doi:https://doi.org/10.1038/nature19328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from NIH (1 R01 CA160335 and 1 R01 CA216991) and from the Avon Foundation for Women (02-2016-020 and 02-2017-005) to D.M. We acknowledge the additional members of the Marchetti lab who have contributed over the years to the work presented.

Author Contributions

MV, DB, and DM wrote the manuscript. All authors edited versions of the manuscript and commented each other contribution. All authors agreed on the manuscript contents.

Competing Interests

Authors declare no competing interests.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA

    Monika Vishnoi

  2. Center for Immunotherapy Research, Houston Methodist Research Institute, Houston, TX, USA

    Debasish Boral

  3. Division of Molecular Medicine/Department of Internal Medicine and Department of Pathology, UNM Comprehensive Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Dario Marchetti

Authors
  1. Monika Vishnoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debasish Boral
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dario Marchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dario Marchetti .

Editor information

Editors and Affiliations

  1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Richard J. Cote

  2. ACTC Lab, Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece

    Evi Lianidou

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Vishnoi, M., Boral, D., Marchetti, D. (2023). Transcriptomic Analysis of CTCs. In: Cote, R.J., Lianidou, E. (eds) Circulating Tumor Cells. Current Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-031-22903-9_11

Download citation

Publish with us

Policies and ethics

Search

Navigation