We had joy, we had fun 1

Other Arrivals and Departures 2

The MRC Festival of Research 3

Research Successes 4

Other news 6

Conferences and awards 6

Our scientists in the limelight 7

Recent publications 8

Message from the Director

Welcome to the summer edition

of the MRC CU newsletters. We

look back at the summer that has

just been and relive some of the

diverse events that - taken

together - showcase our Unit’s

strengths and have brought us

closer as a community. As always,

there is news of all the exciting

research, scientific and other

related achievements of our

students and staff.

To keep up to date with our news,

till the next edition, please visit

our Website, Facebook and

Twitter pages.

With Best Wishes,

Professor Ashok Venkitaraman.

Director, MRC Cancer Unit

We had joy, we had fun…

Looking back at a summer of many visitors

Contents Summer 2018 www.mrc-cu.cam.ac.uk

It wasn’t just the beast from the east and a string of glorious bright days that

visited us this summer. From celebrities to ice-cream, we had it all!

Professor Stephen Toope, the new Vice Chancellor of the University, as part of

his tour of the Biomedical Campus, visited the Unit on the 29th May and had

discussions with the Director and senior group leaders about the Cancer Unit’s

mission, its science, and its direction of travel.

Speaking of travel and the fortuitous friendships it kindles, Dr Christian Frezza

had a chance encounter with the snooker superstar Ronnie O’Sullivan on a plane

to China. Over a pint, in mid-air, Ronnie was curious to find out all about

metabolomics and cancer. True to his word though, when on firmer ground, he

arranged to visit the Cancer Unit on the 31st May. It was a privilege to host the

legendary sportsman, who mingled with staff and students, peered over

microscopes and listened attentively to all the talks that the Frezza group had laid

out for him. A great example of how to communicate our science, its societal

relevance and impact to the world outside of academia.

MRC Cancer Unit

2

The newest additions to the CU family!

In August, Dr Serena Nik-Zainal joined

the Cancer Unit as a faculty member,

an affiliation to be held in conjunction

with her current appointment at the

Department of Medical Genetics

(ADMG). A very warm welcome to

Serena, Andrea Degasperi, Jan

Czarmecki, Scott Shooter, Xueqing

Zou, Tauanne Dias Amarante, Scott

Nanda, Yasin Memari and Helen

Davies from the Nik-Zainal Group!

Hope you enjoy your time at the

Hutch.

Other recent arrivals & departures

We welcome Jianfeng Ge, Tanmoy Mukherjee (Research Associates) and Aisling Redmond (Fitzgerald Group

Research Manager). We would like to wish Shona MacRae, Sine MacDonald, Gianmarco Contino, Callum

Campbell, Garrett Beeghly, Melissa van-Velthoven, Clément Bodineau, and all our summer and work experience

students the very best in their future careers.

Continued from page 1

May was followed by some glorious sunny days when it was time to celebrate

the ‘chiller anniversary’ - to commemorate a year of the rooftop chillers (the

workhorses behind the building’s air-conditioning) not repeating their

catastrophic breakdown the year before, bang in the middle of the hottest week

of that year.

A welcome diversion to the humdrum of daily Hutch business came from the

jingle of the ice-cream van, that the Centre Manager had arranged for that

afternoon in June - soon we had onlookers and visitors from nearby buildings

along with all the happy faces of our own.

As summer paves way to autumn and the start of a new term, the chillers

trudge on, sometimes perilously close to another meltdown, come sunny days,

even as we patiently wait for our turn on the University estates repair list.

Perhaps a quiet testimonial to the unfailing infrastructure and backend service

that the building provides to the research community it houses. Long may it

last!

3

The MRC Festival of Research, 2018

For a fortnight in June, all MRC organisations across the country,

indeed even in other countries across continents, gear up to host a

range of events that highlight the MRC’s mission in medical research

and commitment to public engagement. As part of this, the ever

popular Schools Open Day was back at the CU. On the 19th June,

sixth form students from local schools were given a hands-on tour

of the CU labs, followed by a careers session with scientists at

various stages of their research journeys.

In the labs, the young people scraped

petri dishes and poured over cells under

microscopes, learnt about assay development, not to mention the importance of

accurate pipetting, discovered what

computational modelling and

metabolism had to do with cancer,

and marvelled at the exquisite

regulation of the cell cycle, what

goes wrong with it in cancer and

how scientists are targeting these

Achilles heels. Their questions

were engaging, their feedback later

gratifying! A big thank you to all staff and

students from the CU who volunteered to make this event

possible. More photos of the day are on our Facebook page.

For Festival week, we also chose to highlight our work, its needs and its impacts to our local MP, Heidi Allen.

Over an engaging conversation with the MRC CU’s group leaders and PhD

students, the MP was

given a whistle-stop

tour of our science, a

feel (quite literally!) of

what it is to develop a

tool through years of

research that

potentially improve

patient outcome and a

chance to hear about

experiences and views

from staff and students

relating to recent developments in British politics and its potential impact on

collaborative research.

4

Not all schools have the culture or resources to engage at events such as ours, much that we would have liked to

provide the same experience to all students/children. With this in mind, our staff and students take every

opportunity, despite their busy schedules, to fit in public engagement with schools. Professor Ashok

Venkitaraman gave one such talk in June at the Castle Manor Academy in Haverhill, after which a clearly

moved head teacher thanked Ashok for coming along to talk to his students to inspire them to think that research

was well within their grasp and that everything was possible!

MRC Cancer Unit: Research successes

Cellular identity theft leads to cancer metastasis

The spread of cancers to distant organs, or metastasis, is responsible for the majority of cancer-related deaths.

How cancers develop the capability to spread has remained mostly unclear, however. New research led by Dr.

Sakari Vanharanta at the Unit, has now identified molecular mechanisms that allow cancer cells to acquire

characteristics from other cell types, such as white blood cells, in order to spread and form metastasis.

Each cell in our body carries the same genes. Yet, due to differences in the way cells read their DNA, and

consequently express their genes, tissues behave differently. Gene expression is orchestrated by tissue-specific

networks of gene regulatory elements called transcriptional enhancers, i.e. DNA sequences that control when and

where specific genes should be expressed. Enhancers are therefore critical determinants of cellular identity. The

new work, published in Cancer Discovery, sheds light on how cancer cells read DNA in unique ways, leading to

vastly different behaviours, such as variability in metastatic potential. The work demonstrates how some cancer

cells are able to co-opt tissue-specific enhancers from unrelated cell types in order to activate genes that support

metastatic progression. Through inappropriate enhancer activation, cancer cells thus ‘steal’ features from normal

cells, consequently facilitating metastatic spread.

The new observations provide fundamental insight into a long-standing biological

and clinical problem of metastasis, and they suggest that therapeutic approaches

that would limit the capability of cancer cells to aberrantly activate enhancers

could inhibit metastasis in patients.

The study entitled ‘NF-κB–Dependent Lymphoid Enhancer Co-option Promotes Renal

Carcinoma Metastasis’ by Rodrigues et al. has been published in Cancer Discovery

in June 2018.

The article has also been covered as a feature by New Scientist, referenced by the Daily Mail and highlighted on

the MRC website.

Continued from page 3

5

Establishing organoid cultures as a new tool to study evolution and precision therapeutics

for a deadly solid tumour with very poor prognosis

Models of cancer are needed to test drugs and understand how they develop. Few models exist for cancer of the

gullet (oesophagus). This month Nature Communications

Editors' Highlight on Stem cell and Disease as well as Genomes

and Epigenomes has selected a collaborative study between

the Sanger Institute (Mathew Garnet) and the MRC Cancer

Unit (Rebecca Fitzgerald), which established a panel of

organoid cultures derived from Oesophageal

Adenocarcinoma. These 3D cultures which were established

from patients undergoing extensive molecular

characterisation as part of the International Cancer Genome

Consortium. The authors were able to show that these

organoids faithfully recapitulated the morphological, functional

and genetic features of tumours and the cultures yielded

interesting data on tumour evolution and susceptibility to chemotherapy and molecularly targeted agents. This

provides the community with a powerful translational tool for this very poor prognosis disease.

The study entitled ‘Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for

clonality studies and precision therapeutics’ by Li et al. was published in Nature Communications in July 2018.

Novel Uses of Computational Modelling to understand the role of Membrane Transport in Cancer

Membrane transporters are proteins used to maintain the concentration gradients of various chemicals between

the exterior and interior of a cell. The gradients of these chemicals are then generally used for processes like

maintaining cell size (osmotic regulation), and are also signalling molecules for processes like cell migration and

division.

In their new publication in Nature Communications, researchers from Dr Ben Hall’s group at the MRC Cancer

Unit show for the first time that alterations in the expression of these membrane transporters consistently occurs

in all cancers. Going further, the researchers were able to construct a computational model of the key chemical

gradients and transporters within a cell, and show precisely how changes in the expression of them can alter

cancer cell behaviour. The research is a start at understanding how these proteins can be used as potential markers

or drug targets in the future. The study entitled ‘Exploring the role of stromal osmoregulation in cancer and disease

using executable modelling’ by Shorthouse et al. was published in Nature Communications in August 2018.

Continued from page 4

6

Conferences from the CU

In June Dr Christian Frezza and his team

hosted the first workshop on Metabolomics

sponsored by the “TRANSMIT” PhD programme

funded by the Marie Curie Innovative Training

Network. The event, attended by several

students, included presentation on the principles

of metabolomics, hands-on experience of liquid

chromatography and mass-spectrometry as well

as analyses of small molecule metabolites. Dr

Frezza was also a lead organiser of the 4th

Abcam “Cancer and Metabolism”

conference (25-27 June). The congenial meeting

had a great line-up of speakers who dwelt on the

impact of metabolic factors on tumour growth

and metastasis, and other hot topics in the field,

such as the analysis of metabolism in vivo and at

subcellular level. Saiful Effendi Syafruddin from the

CU was one of the poster prize winners at the

meeting. Well done Fendi!

Dr Ben Hall and colleagues organised the first

“Discrete models and formal verification in

biology” meeting in August. Attended by 40

academic and industrial scientists from 8

countries the conference created a great platform

for the specialist community to come together to

foster new collaborations and discuss how to

highlight developments in the field.

Other News 70 years young and still going

strong! All of the Hutch gathered

over tea and cakes to celebrate the

special birthday of one of its most

loved members - Jacki in the canteen.

It was a special occasion to

remember the lovely person who

keeps us all fed and watered, always

with a smile and a kind word. Here’s

wishing her many more years of

happiness!

Congratulations to Sarah

Davidson, PhD student in the

Shields lab, for winning one of the

three best poster prizes at the “8th

international conference on tumour

microenvironment progression

therapy and prevention”, held in

Lisbon in June.

Prof. Ashok Venkitaraman

was invited to deliver the

President’s Research Seminar at Memorial Sloan Kettering Cancer Center, New York in June.

Upcoming events Hutchison MRC Annual Retreat – 30

November 2018.

Upcoming events

7

Our scientists in the limelight

Professor Ashok Venkitaraman

received his Basser Global Prize at an

award ceremony held at UPenn,

Philadelphia in May. Congratulations

to Ashok!

Dr Sakari Vanharanta spoke at a

recent event to celebrate confluence

across various disciplines and cultures.

The public event themed “ Arts Meet

Science” held at the quirky Beaconsfield

Gallery, Vauxhall, London (with trains

crisscrossing overhead) was organised

by the Finnish Institute. In addition to

Sakari’s talk ‘Open Questions in Cancer

Biology’ the event featured The Trace, a

multidisciplinry performance developed

by Hannaleena Heiska, a visual artist and

also featured Minna Tervamäki, a

dancer/choreographer and the prima

ballerina at the Finnish National Ballet.

8

Recent publications

1: Pell VR, Spiroski AM, Mulvey J, Burger N, Costa ASH, Logan A, Gruszczyk AV, Rosa T, James AM, Frezza C,

Murphy MP, Krieg T. Ischemic preconditioning protects against cardiac ischemia reperfusion injury

without affecting succinate accumulation or oxidation. J Mol Cell Cardiol. 2018 Aug 14. pii: S0022-

2828(18)30792-2. doi: 10.1016/j.yjmcc.2018.08.010. [Epub ahead of print] PubMed PMID: 30118790.

2: Zaini MN, Patel SA, Syafruddin SE, Rodrigues P, Vanharanta S. Endogenous HIF2A reporter systems for

high-throughput functional screening. Sci Rep. 2018 Aug 13;8(1):12063. doi: 10.1038/s41598-018-30499-2.

PubMed PMID: 30104738; PubMed Central PMCID: PMC6089976.

3: Januszewicz W, Tan WK, Lehovsky K, Debiram-Beecham I, Nuckcheddy T, Moist S, Kadri S, di Pietro M,

Boussioutas A, Shaheen NJ, Katzka DA, Dellon ES, Fitzgerald RC; BEST 1 and BEST2 study investigators.

Safety and acceptability of a non-endoscopic esophageal sampling device - Cytosponge(®): a

systematic review of multi-center data. Clin Gastroenterol Hepatol. 2018 Aug 9. pii: S1542-

3565(18)30809-7. doi: 10.1016/j.cgh.2018.07.043. [Epub ahead of print] PubMed PMID: 30099104.

4: Smyth EC, Fitzgerald RC. MUC16 Mutations and Prognosis in Gastric Cancer: A Little Goes a Long

Way. JAMA Oncol. 2018 Aug 9. doi: 10.1001/jamaoncol.2018.2803. [Epub ahead of print] PubMed PMID:

30098141.

5: Sami SS, Iyer PG, Pophali P, Halland M, di Pietro M, Ortiz-Fernandez-Sordo J, White JR, Johnson M, Guha IN,

Fitzgerald RC, Ragunath K. Acceptability, Accuracy and Safety of Disposable Transnasal Capsule

Endoscopy for Barrett's Esophagus Screening. Clin Gastroenterol Hepatol. 2018 Aug 2. pii: S1542-

3565(18)30743-2. doi: 10.1016/j.cgh.2018.07.019. [Epub ahead of print] PubMed PMID: 30081223.

6: Offman J, Muldrew B, O'Donovan M, Debiram-Beecham I, Pesola F, Kaimi I, Smith SG, Wilson A, Khan Z,

Lao-Sirieix P, Aigret B, Walter FM, Rubin G, Morris S, Jackson C, Sasieni P, Fitzgerald RC; BEST3 Trial team.

Barrett's oESophagus trial 3 (BEST3): study protocol for a randomised controlled trial comparing

the Cytosponge-TFF3 test with usual care to facilitate the diagnosis of oesophageal pre-cancer in

primary care patients with chronic acid reflux. BMC Cancer. 2018 Aug 3;18(1):784. doi: 10.1186/s12885-

018-4664-3. PubMed PMID: 30075763; PubMed Central PMCID: PMC6091067.

7: Shorthouse D, Riedel A, Kerr E, Pedro L, Bihary D, Samarajiwa S, Martins CP, Shields J, Hall BA. Exploring

the role of stromal osmoregulation in cancer and disease using executable modelling. Nat Commun.

9

2018 Aug 1;9(1):3011. doi: 10.1038/s41467-018-05414-y. PubMed PMID: 30069015; PubMed Central PMCID:

PMC6070494.

8: Drusian L, Nigro EA, Mannella V, Pagliarini R, Pema M, Costa ASH, Benigni F, Larcher A, Chiaravalli M, Gaude

E, Montorsi F, Capitanio U, Musco G, Frezza C, Boletta A. mTORC1 Upregulation Leads to

Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma. Cell

Rep. 2018 Jul 31;24(5):1093-1104.e6. doi: 10.1016/j.celrep.2018.06.106. PubMed PMID: 30067967.

9: Li X, Francies HE, Secrier M, Perner J, Miremadi A, Galeano-Dalmau N, Barendt WJ, Letchford L, Leyden

GM, Goffin EK, Barthorpe A, Lightfoot H, Chen E, Gilbert J, Noorani A, Devonshire G, Bower L, Grantham A,

MacRae S, Grehan N, Wedge DC, Fitzgerald RC, Garnett MJ. Organoid cultures recapitulate esophageal

adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics.

Nat Commun. 2018 Jul 30;9(1):2983. doi:10.1038/s41467-018-05190-9. PubMed PMID: 30061675; PubMed

Central PMCID: PMC6065407.

10: Muliaditan T, Caron J, Okesola M, Opzoomer JW, Kosti P, Georgouli M, Gordon P, Lall S, Kuzeva DM,

Pedro L, Shields JD, Gillett CE, Diebold SS, Sanz-Moreno V, Ng T, Hoste E, Arnold JN. Macrophages are

exploited from an innate wound healing response to facilitate cancer metastasis. Nat Commun.

2018 Jul 27;9(1):2951. doi: 10.1038/s41467-018-05346-7. PubMed PMID: 30054470; PubMed Central PMCID:

PMC6063977.

11: Frezza C. Histidine metabolism boosts cancer therapy. Nature. 2018Jul;559(7715):484-485. doi:

10.1038/d41586-018-05573-4. PubMed PMID: 30030511.

12: O'Donovan M, Fitzgerald RC. Screening for Barrett's Esophagus: Are New High-Volume Methods

Feasible? Dig Dis Sci. 2018 Jul 11. doi: 10.1007/s10620-018-5192-3. [Epub ahead of print] Review. PubMed

PMID: 29995243; PubMed Central PMCID: PMC6061133.

13: Kruspig B, Monteverde T, Neidler S, Hock A, Kerr E, Nixon C, Clark W, Hedley A, Laing S, Coffelt SB, Le

Quesne J, Dick C, Vousden K, Martins CP, Murphy DJ. The ERBB network facilitates KRAS-driven lung

tumorigenesis. Sci Transl Med. 2018 Jun 20;10(446). pii: eaao2565. doi: 10.1126/scitranslmed.aao2565.

PubMed PMID: 29925636.

14: Li X, Kleeman S, Coburn SB, Fumagalli C, Perner J, Jammula S, Pfeiffer RM,Orzolek L, Hao H, Taylor PR,

Miremadi A, Galeano-Dalmau N, Lao-Sirieix P, Tennyson M, MacRae S, Cook MB, Fitzgerald RC. Selection and

10

Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus.

Gastroenterology. 2018 Jun 12. pii: S0016-5085(18)34643-2. doi: 10.1053/j.gastro.2018.05.050. [Epub ahead of

print] PubMed PMID: 29906417.

15: Rodrigues P, Patel SA, Harewood L, Olan I, Vojtasova E, Syafruddin SE, Zaini MN, Richardson EK, Burge J,

Warren AY, Stewart GD, Saeb-Parsy K, Samarajiwa SA, Vanharanta S. NF-κB-Dependent Lymphoid

Enhancer Co-option Promotes Renal Carcinoma Metastasis. Cancer Discov. 2018 Jul;8(7):850-865. doi:

10.1158/2159-8290.CD-17-1211. Epub 2018 Jun 6. PubMed PMID: 29875134; PubMed Central PMCID:

PMC6031301.

16: Fitzgerald RC. Organ-preserving approaches in oesophageal cancer. Lancet Oncol. 2018

Jul;19(7):858-859. doi: 10.1016/S1470-2045(18)30291-2. Epub 2018 Jun 1. PubMed PMID: 29861117; PubMed

Central PMCID: PMC6078177.

17: Fewings E, Larionov A, Redman J, Goldgraben MA, Scarth J, Richardson S, Brewer C, Davidson R, Ellis I,

Evans DG, Halliday D, Izatt L, Marks P, McConnell V, Verbist L, Mayes R, Clark GR, Hadfield J, Chin SF, Teixeira

MR, Giger OT, Hardwick R, di Pietro M, O'Donovan M, Pharoah P, Caldas C, Fitzgerald RC, Tischkowitz M.

Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with

hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.

Lancet Gastroenterol Hepatol. 2018 Jul;3(7):489-498. doi: 10.1016/S2468-1253(18)30079-7. Epub 2018 Apr 27.

PubMed PMID: 29706558; PubMed Central PMCID: PMC5992580.

18: Periasamy J, Kurdekar V, Jasti S, Nijaguna MB, Boggaram S, Hurakadli MA, Raina D, Kurup LM, Chintha C,

Manjunath K, Goyal A, Sadasivam G, Bharatham K, Padigaru M, Potluri V, Venkitaraman AR. Targeting

Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-

Dependent Signaling. Cell Chem Biol. 2018 Jun 21;25(6):677-690.e12. doi: 10.1016/j.chembiol.2018.02.012.

Epub 2018 Mar 29. PubMed PMID: 29606576; PubMed Central PMCID: PMC6015222.

19: Neves AA, Di Pietro M, O'Donovan M, Waterhouse DJ, Bohndiek SE, Brindle KM, Fitzgerald RC.

Detection of early neoplasia in Barrett's esophagus using lectin-based near-infrared imaging: an ex

vivo study on human tissue. Endoscopy. 2018 Jun;50(6):618-625. doi: 10.1055/s-0043-124080. Epub 2018 Jan

17. PubMed PMID: 29342490.

11

MRC Cancer Unit

University of Cambridge

Hutchison/MRC Research Centre

Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ

Tel: 01223 763240

Email: contact@mrc-cu.cam.ac.uk

www.mrc-cu.cam.ac.uk

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