TUMOUR DEVELOPMENT

My group studies mechanisms of tumour tolerance and progression driven by tumour infiltrated myeloid cell populations, with the overarching aim of identifying novel molecular targets for the development of immunotherapies. Our work demonstrates that targeting Myeloid Derived Suppressor Cells (MDSC) restores immune-system control over disease progression, offering novel therapeutic opportunities for breast cancer.

Transcriptome analysis has been extensively used to understand heterogeneity of breast cancer and to predict response to therapy and patient outcome. Conventional gene expression profiling of bulk complex cell populations is often dominated by the major compartment, thus masking low-abundant populations and denying cellular diversity. We use massively-parallel single-cell transcriptomic technologies (scRNA-seq) to characterise breast tumour cell diversity, simultaneously analysing cancer cell heterogeneity and tumour-associated stromal cells, with a particular focus in the infiltrating immune system.

Integration of scRNAseq technologies provides high-resolution molecular phenotyping of breast cancer, allowing us to accurately map regulatory networks of tumour development. Understanding the molecular mechanisms of the cancer-to-immune cell communication is essential for the development of immunotherapies.

Selected Publications

F Valdés-Mora, CM Gould, Y Colino-Sanguino, W Qu, JZ Song, KM Taylor, FA Buske, AL Statham, SS Nair, NJ Armstrong, JG Kench, KML Lee, LG Horvath, M Qiu, A Ilinykh, NS Yeo-Teh, D Gallego-Ortega, C Stirzaker and SJ Clark. Novel contribution of acetylated histone variant H2A.Z in activation of neo-enhancers in prostate cancer. Nature Comms 2017 In press.

SR Oakes, D Gallego-Ortega, PM Stanford, S Junankar, WY Au, Z Kikhtyak, AV Korff, CM Sergio, AMK Law, LE Castillo, SL Allerdice, AIJ Young, C Piggin, B Whittle, E Bertram, MJ Naylor, DL Roden, J Donovan, A Korennykh, CC Goodnow, MK O’Bryan and CJ Ormandy. A mutation in the viral sensor oligoadenylate synthase 2 causes failure of lactation. PLoS Genetics 2017 In press.

F. Valdes-Mora, WJ. Locke, E. Bandres, D. Gallego-Ortega, P. Cejas, MA. Garcia-Cabezas, Y. Colino-Sanguino, J. Feliu, T. Gomez del Pulgar and JC. Lacal. Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer. Oncotarget 2017, Apr 18;8(16):26755-26770.

C. Vennin, VT. Chin, SC. Warren, MC. Lucas, D. Herrmann, A. Magenau,P. Melenec, SN. Walters, G. Monte-Nieto, JRW. Conway, M. Nobis, AH. Allam, RA. McCloy, N. Currey, M. Pinese, A. Boulghourjian, A. Zaratzian, ASA. Adam, C. Heu, AM. Nagrial, A. Chou, A. Steinmann, A. Drury, D. Froio, M. Giry-Laterriere, NLE. Harris, T. Phan, R. Jain, W. Weninger, EJ. McGhee, R. Whan, AL. Johns, JS. Samra, L. Chantrill, AJ. Gill, M. Kohonen-Corish, RP. Harvey, AV. Biankin, APGI, TRJ. Evans, KI. Anderson, ST. Grey, CJ. Ormandy, D. Gallego-Ortega, Y. Wang, MS. Samuel, OJ. Sansom, A. Burgess, TR. Cox, JP. Morton, M. Pajic and P Timpson.Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy and the onset of the metastatic niche. Science Trans Med 2017, April 9(384). doi: 10.1126/scitranslmed.aai8504.

AMK. Law, E. Lim, CJ. Ormandy and #D. Gallego-Ortega. The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy. Endocr Relat Cancer 2017, Feb 13. pii:ERC-16-0404. doi: 10.1530/ERC-16-0404. (# Corresponding author).

AIJ. Young, AMK. Law, L. Castillo, S. Chong, HD. Cullen, M. Koehler, S. Herzog, T. Brummer, EF. Lee, WD. Fairlie, MC. Lucas, D. Herrmann, A. Allam, P. Timpson, DN. Watkins, EKA. Millar, SA. O’Toole, D. Gallego-Ortega, *CJ. Ormandy and *SR. Oakes. MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib. Breast Cancer Res. 2016. Dec 8;18(1):125. (* contributed equally).

CL. Piggin, DL. Roden, D. Gallego-Ortega, HJ. Lee, SR. Oakes and CJ. Ormandy. ELF5 isoform expression is tissue-specific and significantly altered in cancer. Breast Cancer Res. 2016, Jan 7;18(1):4. doi: 10.1186/s13058-015-0666-0.

#D. Gallego-Ortega, A. Ledger, DL. Roden, AMK. Law, A. Magenau, Z. Kikhtyak, C. Cho, SL. Allerdice, HJ. Lee, F. Valdes-Mora, D. Herrmann, R. Salomon, AIJ. Young, BY. Lee, CM. Sergio, W. Kaplan, CL. Piggin, JRW. Conway, B. Rabinovich, EKA. Millar, SR. Oakes, T. Chtanova, A. Swarbrick, MJ. Naylor, S. O’Toole, AR. Green, P. Timpson, JMW. Gee, IO. Ellis, SJ. Clark and #CJ. Ormandy. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells. PLoS Biol. 2015 Dec 30;13(12):e1002330. (# Corresponding Author).

Z. Erami, D. Herrmann, M. Nobis, EJ. McGhee, W. Leung, N. Reischmann, A. Mrowinska, JP. Schwarz, S. Kadir, JRW. Conway, SA. Karim, C. Steele, D. Morran, D. Gallego-Ortega, A. Magenau, RA. Ridgway, AKM. Law, SN. Walters, ST. Grey, L. Zhang, H. Herzog, EC. Hardeman, PW. Gunning, CJ. Ormandy, TRJ. Evans, D. Strathdee, OJ. Sansom, JP. Morton, KI. Anderson and P. Timpson. Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease and drug-dependent dynamic regulation of cell-cell junctions in live tissue. Cell Rep. 2015 Dec 22. pii: S2211-1247(15)01433-3

Junankar S, *Baker LA, *Roden DL, Nair R, Elsworth B, Gallego-Ortega D, Lacaze P, Cazet A, Nikolic I, Teo WS, Yang J, McFarland A, Harvey K, Naylor MJ, Lakhani SR, Simpson PT, Raghavendra A, Saunus J, Madore J, Kaplan W, Ormandy C, Millar EK, O'Toole S, Yun K, Swarbrick A. ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. Nat Comms. 2015 Mar 27;6:6548. (* Contributed equally)

*SR. Oakes, *D. Gallego-Ortega and CJ. Ormandy. The mammary cellular hierarchy and breast cancer. Cell Mol Life Sci. 2014 Nov;71(22):4301-24. (* Contributed equally)

D. Gallego-Ortega, SR. Oakes, HJ. Lee, CL. Piggin, CJ. Ormandy. ELF5, normal mammary development and the heterogeneous phenotypes of breast cancer. Breast Cancer Management, 2013; 2(6):489-498.

A. Stone, MJ. Cowley, F. Valdes-Mora, RA. McCloy, CM. Sergio, D. Gallego-Ortega, CE Caldon, CJ. Ormandy, AV. Biankin, JMW Gee, RI. Nicholson, CG. Print, SJ. Clark, RL. Sutherland and EA. Musgrove. BCL-2 hypermethylation is a potential biomarker of sensitivity to anti-mitotic chemotherapy in endocrine-resistant breast cancer. Mol Cancer Ther. 2013; 12(9):1874-85.

HJ. Lee, D. Gallego-Ortega, A. Ledger, D. Schramek, P. Joshi, MM. Swarc, C. Cho, JP. Lydon, R. Khokha, JM. Penninger, and CJ. Ormandy. Progesterone drives mammary secretory differentiation via RankL-induction of Elf5 in luminal progenitor cells. Development. 2013; 140(7):1397-401.

DR. Croucher, F. Hochgräfe, L. Zhang, L. Liu, RJ. Lyons, D. Rickwood, CM. Tactacan, BC. Browne, N. Ali, H. Chan, RF. Shearer, D. Gallego-Ortega, DN. Saunders, A. Swarbrick and R. Daly. A novel signaling pathway in basal breast cancer involving Lyn and the atypical kinase SgK269/PEAK1. Cancer Res. 2013; 73(6):1969-80

*M. Kalyuga - *D. Gallego-Ortega, H. Lee, M. Cowley, CE. Caldon, A. Stone, S. Allerdice, F. Valdes-Mora, R. Launchbury, A. Statham, N. Armstrong, C. Alles, A. Young, A. Egger, W. Au, C. Piggin, C. Evans, T. Brummer, W. Kaplan, JMW. Gee, RI. Nicholson, RL. Sutherland, A. Swarbrick, MJ. Naylor, S. Clark, J. Carroll and CJ. Ormandy. ELF5 transcriptionally specifies basal from luminal breast cancer and underpins the acquisition of antiestrogen resistance. PLoS Biol. 2012;10(12):e1001461. (* Joint first authors).

C. Ortiz-Padilla, D. Gallego-Ortega, BC. Browne, F. Hochgräfe, CE. Caldon, RJ. Lyons, DR. Croucher, D. Rickwood, CJ. Ormandy, T. Brummer and RJ. Daly. Functional characterization of cancer-associated Gab1 mutation. Oncogene. 2013; 23;32(21):2696-702.

*HJ. Lee - RA. Hinshelwood, T. Bouras, D. Gallego-Ortega, F. Valdes-Mora, JE. Visvader, ^SJ Clark and ^CJ. Ormandy. Lineage Specific Methylation of the Elf5 Promoter in Mammary Epithelial Cells. Stem Cells, 2011; 29(10):1611-9. (^* Contributed equally)

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