Shackleton group

Cancer Development and Treatment

Key terms: Medical Oncology, Melanoma, Cancer Therapeutics


Group Leader
Prof Mark Shackleton

mark.shackleton@monash.edu

Research Fellows
Dr Gamze Kuser Abali

Research Assistants
Pacman Szeto
Angela Peng
Dr YouFang Zhang


2017 Mark Shackleton's Cancer Development and Treatment Laboratory members
Front (L to R): Angela Peng, Pacman Szeto, Dr Akiko Shimizu 
Back (L to R): Dr Fumihito Noguchi, Prof Mark Shackleton, YouFang Zhang

Absent: Dr Gamze Kuser Abali 

Research overview

The Cancer Development and Treatment laboratory is located on Level 4 of the Burnet Institute, Alfred Medical Research and Education Precinct (AMREP). The laboratory aims to elucidate mechanisms of cancer initiation and progression, and to develop cancer therapies. Our main disease focus is on melanoma, a deadly type of skin cancer for which new and more effective therapy are rapidly emerging. We engage a wide-range of techniques and resources to support our work, including extensive banks of patient tissues and transgenic mice. Our current research includes studies of intra-tumoral heterogeneity, cancer evolution, the Hippo molecular signalling pathway and normal and neoplastic melanocyte development.

Enquiries welcome from potential honours, MD or PhD students.

Intra-tumoral heterogeneity

Shackleton Research1

One of the most important discoveries in cancer over the past decade has been revelation of the extent of disease heterogeneity within individual patients. This heterogeneity is seen on multiple levels - cellular, genetic, epigenetic - and even within individual tumours. These factors influence disease outcomes in patients such as metastasis and therapy resistance. Understanding the causes and consequences of cancer heterogeneity and identifying approaches to exploit or overcome it are major goals in our lab.

HIPPO - A new signalling pathway in cancer

The recently discovered Hippo molecular signalling pathway is a key regulatory mechanism in normal development and multiple cancers including melanoma. Data is rapidly emerging that central mediators of Hippo signalling, such as the oncoprotein YAP, drive the growth, survival and metastasis of melanoma. These studies are spurring the development of novel treatments that inhibit YAP function and are expected to be effective in a wide range of cancers.

Melanocyte development

In order to understand melanocytic transformation, the elucidation of normal melanocyte development and homeostasis is essential. Towards this, we are pioneering novel cell isolation techniques to purify melanocytes for the evaluation of mechanisms that facilitate melanoma formation.

Key techniques employed in our research include: patient derived xenografting (PDX), transgenic mouse modelling, cell culture, flow cytometry, immunohistochemistry, genomics and various molecular techniques.

Publications

Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, Patch AM, Kakavand H, Alexandrov L, Burke H, Jakrot V, Kazakoff S, Holmes O, Leonard C, Wood S, Xu Q, Waddell N, Tembe V, Pupo GM, De Paoli R, Vilain RE, Shang P, Schramm SJ, Pritchard A, Dutton-Regester K, Fitzgerald A, Shang CA, Grimmond SM, Yang YH, Kefford RF, Hersey P, Long GV, Cebon J, Shackleton M, Spillane AJ, Saw RP, Pearson JV, Thompson JF, Scolyer RA, Mann GJ. Whole genome landscapes of major melanoma subtypes. Nature 2017 May 11;545(7653):175-180

Noguchi F, Inui S, Fedele CF, Shackleton M* and Itami S*. Calcium-dependent enhancement by extracellular acidity of the cytotoxicity of mitochondrial inhibitors against melanoma. Mol Cancer Ther 2017 May;16(5):936-947 *Equal

Wong SQ, Raleigh J*, Callahan J*, Vergara I*, Ftouni S, Hatzimihalis A, Colebatch A, Li J, Semple T, Doig K, Mintoff CM, Sinha D, Yeh P, Silva MJ, Mir Arnau G, Cullinane C, Alsop K, Thorne H, Bowtell D, Gyorki D, Kee D, Brady B, Dawson MA, Papenfuss AT, Shackleton M, Hicks R, McArthur GA, Sandhu S† and Dawson SJ†. Predictive utility of ctDNA and FDG-PET in melanoma metastasis and therapy. J Clin Oncol Prec Oncol 2017 In press *†Equal

Eskiocak U, Ramesh V, Zhao Z, Yuan SW, Gill J, Wang M, Vandergriff T, Shackleton M, Quintana E, Johnson TM, DeBerardinis RJ, and Morrison SJ. Synergy of ion transporter and MAP kinase pathway inhibitors in melanoma. Nat Commun 2016 7:12336

Ebert LM, Tan LY, Johan Z, Myo Min KK, Cockshell MP, Parham KA, Betterman KL, Szeto P, Boyle S, Silva L, Peng A, Zhang YF, Ruszkiewicz A, Zannettino ACW, Gronthos S, Koblar S, Harvey NL, Lopez AF, Shackleton M and Bonder CS. Desmoglein-2 is a novel surface marker of endothelial and hematopoietic progenitor cells and plays an important role in blood vessel formation. Angiogenesis 2016 19(4):463-86

Tan LY, Mintoff C, Johan MZ, Ebert BW, Fedele C, Zhang YF, Szeto P, Sheppard KE, McArthur GA, Foster-Smith E, Ruszkiewicz A, Brown MP, Bonder CS*, Shackleton M*, and Ebert LM*. Desmoglein-2 (DSG2) is a key regulator of vasculogenic mimicry and associated with poor clinical outcome in human melanoma. Oncotarget 2016 7(29):46492-46508*Equal

Boyle SE, Fedele CG, Corbin V, Wybacz E, Szeto P, Young R, Lewin J, Wong A, Fuller R, Spillane J, Speakman D, Donahoe S, Pohl M, Gyorki D, Henderson MA, Johnstone R, Papenfuss AT and Shackleton M. CD271 expression on patient melanoma cells is unstable and unlinked to tumorigenicity. Cancer Research 2016 76 (13):3965-3977

Alsop K, Thorne H, Sandhu S, Hamilton A, Mintoff C, Christie E, Spruyt O, Williams S, McNally O, Mileshkin L, Ananda S, Hallo J, Loi S, Scott C, Savas P, Devereux L, Leditschke J, O’Brien P, Gunawardena S, Hampson C, Strachan K, Jaravaza RD, Francis V, Young G, Ranson D, Samaranayake R, Madadin M, Stevens D, Boyle S, Fedele C, Topp M, Ho G, Teo ZL, Taylor RA, Papargiris MM, Lawrence MG, Wang H, Risbridger GP Haynes NM, Medon M, Johnstone RW, Vidacs E, Mir Arnau G, Vergara I, Papenfuss AT, McArthur G, Waring P, Carvosso S, Angel C, Gyorki D, Solomon B, Mitchell G, Shanley S, Francis P, Dawson SJ, Haffenden A, Tidball E, Volchek M, Pyman J, Cordner S, the Melbourne Melanoma Project, the Australian Ovarian Cancer Study Group, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Shackleton M and Bowtell D.  An effective community based model of rapid autopsy in end-stage cancer patients. Nat Biotech 2016 4(10):1010-1014.

Wong SQ, Waldeck K, Vergara IA, Schröder J, Madore J, Wilmot J, Colebatch A, Johnston M, Li J, Lupat R, Semple T, Arnau GM 1, Fellowes A, Cullinane C, Hayward N, Shackleton M, Sandhu S, Bowtell DL , Johnstone RW, Fox SB, McArthur GA, Papenfuss AT, Scolyer RA, Gill AJ, Hicks RJ, Tothill RW. Viral-negative Merkel cell carcinomas of the skin harbour distinct mutational profiles and oncogenic drivers. Cancer Res 2015 75(24):5228-34

Dewaele M, Tabaglio T, Willekens K, Bezzi M, Teo SX, Low DHP, Koh C, Rambow F, Fiers M, Rogiers A, Radaelli E, Al-Haddawi M, Tan SY, Hermans E, Amant F, Yan H, Lakshmanan M, Koumar RC, Lim ST, Derheimer FA, Campbell RM, Bonday Z, Tergaonkar V, Shackleton M, Blattner C, Marine JC and Guccione E. Enhanced MDM4 exon 6 inclusion is a widespread oncogenic mechanism and a clinically- compatible therapeutic target. J Clin Invest 2015 26(1):68-84

Wilmott JS, Field MA, Johansson PA, Kakavand H, Shang P, De Paoli-Iseppi R, Vilain R, Pupo GM, Tembe V, Jakrot V, Shang CA, Cebon J, Shackleton M, Fitzgerald A, Thompson JF , Hayward NK, Graham J. Mann GJ, Scolyer RA. Tumour procurement, DNA extraction, coverage analysis and optimisation of mutation-detection algorithms for human melanoma genomes. Pathology 2015 Dec;47(7):683-93

Ramsdale R, Jorissen RN Li F, Al-Obaidi S, Ward T, Sheppard K, Pearson RB, Boyle S, Shackleton M, Bollag G, Tulchinsky E, Rizos H, McArthur GA, Dhillon AS and Ferrao PT. c-JUN is a critical mediator of melanoma cell survival and phenotype-switching during early adaptation to BRAF/MEK inhibitor therapy. Sci Sig 2015 Aug 18;8(390):ra82

Puzanov I, Amaravadi RK, McArthur G, Flaherty F, Chapman P, Sosman JA, Ribas A, Shackleton M, Hwu P, Chmielowski B, Nolop K, Lin PS and Kim KB. Long-term Outcome in BRAFV600E Melanoma Patients Treated With Vemurafenib: Patterns of Disease Progression and Clinical Management of Limited Progression. Eur J Cancer 2015 Jul;51(11):1435-43

Patch A-M, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, Nones K, Cowin P, Alsop K, Bailey PJ, Kasshan KS, Newell F, Quinn MCJ, Kazakoff S, Quek K, Wilhelm-Benartzi C, Curry E, Leong HS, The Australian Ovarian Cancer Study Group, Hamilton A, Mileshkin L, Au-Yeung G, Kennedy C, Hung J, Chiew Y-E, Harnett P, Friedlander M, Quinn M, Pyman J, Cordner S, O’Brien P, Leditschke J, Young G, Strachan K, Waring P, Azar W, Mitchell C, Traficante N, Thorne H, Shackleton M, Miller DK, Arnau GM, Tothill R, Holloway T, Semple T, Harliwong I, Nourse C, Nourbakhsh E, Manning S, Idrisoglu S, Bruxner TJC, Christ AN, Poudel B, Holmes O, Anderson M, Leonard C, Lonie A, Hall N, Wood S, Taylor DF, Xu Q, Fink JL, Waddell N, Drapkin R, Stronach E, H, Brown B, Jewell A, Nagaraj SH, Markham E, Wilson PJ, Ellul J, McNally O, Doyle M, Vedururu R, Stewart C, Lengyel E, Pearson JV, Waddell N,DeFazio A, Grimmond SM and Bowtell DDL. Whole genome characterisation of chemo-resistant ovarian cancer. Nature 2015 May 28;521(7553):489-94

Schroeder J, Hsu A, Boyle S, MacIntyre G, Cmero M, Tothill RW, Johnstone RW, Shackleton M & Papenfuss AT. Socrates: Identification of genomic rearrangements in tumour genomes by re-aligning soft clipped reads. Bioinformatics 2014 (8) 1064-1072

Quintana E, Piskounova E, Shackleton M, Weinberg D, Eskiocak U, Fullen DR, Johnson TM & Morrison SJ. Human melanoma metastasis in NSG mice correlates with clinical outcome in patients. Sci Transl Med 2012 4:159ra149

Gembarska A, Luciani F, Fedele C, Russell E, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J,  Yip D, Goydos J, Haigh J.J, Haupt Y, Larue ,  Jochemsen A, Shi H, 4  Moriceau G, Roger  Lo R.S, Ghanem G,  Shackleton M, Bernal F & Marine J.C. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 2012 18:1239-47

Tikoo A, Roh V, Montgomery KG,  Ivetac I, Waring P, Pelzer R, Hare L, Shackleton M,  Humbert P, and Phillips WA. Physiological levels of Pik3caH1047R mutation in the mouse mammary gland results in ductal hyperplasia and formation of ER?-positive tumors. PLoS ONE May 2012 7 (5) e36924

Quintana E*, Shackleton M*, Foster H, Fullen DR, Sabel MS, Johnson TM & Morrison SJ. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 2010 Nov 16;18(5):510-23. *Equal

Shackleton M. Moving targets that drive tumor propagation. N Eng J Med. 2010;363(9):885-886

Shackleton M, Quintana E. Progress in understanding melanoma propagation. Mol Oncol. 2010 Oct;4(5):451-7

Shackleton M. Normal stem cells and cancer stem cells: similar and different. Stem Cancer Biol. 2010 April;20(2):85-92

Shackleton M, Quintana E, Morrison SJ. Cancer cell heterogeneity: clonal evolution and cancer stem cells. Cell. 2009 Sep 4;138(5):822-9

Shackleton M, O’Reilly LA, Sutherland KD, Bath ML, Ellis S, Strasser A, Visvader JE, Lindeman GJ. Impaired lactation in mice expressing dominant-interfering FADD in mammary epithelium. Dev Dyn 2009 Apr;238(4):1010-6

Quintana E*, Shackleton M*, Fullen DR, Sabel MS, Johnson TM & Morrison SJ. Efficient tumor formation by single human melanoma cells. Nature 2008 December 4; 456 (7222):593-598. *Equal

Vaillant, F, Asselin-Labat ML, Shackleton M, Forrest N, Lindeman GJ and Visvader JE. The mammary progenitor marker CD61 identifies cancer stem cells in mouse models of mammary tumourigenesis. Cancer Research 2008 Oct 1;68(19):7711-7

Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J, Lindeman GJ and Visvader JE. Gata-3, an essential regulator of mammary gland morphogenesis and luminal cell differentiation. Nat Cell Biol. 2007 Feb;9(2):201-9

Asselin-Labat ML, Shackleton M, Stingl J, Vaillant F, Visvader JE, Eaves CJ, Lindeman GJ. Steroid hormone receptor status of mouse mammary stem cells. J Natl Cancer Inst. 2006 98: 1011-1014

Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ. Purification and unique properties of mammary epithelial stem cells. Nature 2006 Feb 23; 439 (7079):993-7

Shackleton M*, Vaillant F*, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE. Generation of a functional mammary gland from a single stem cell. Nature 2006 Jan 5;439 (7072):84-8. *Equal