Research

Barrett’s oesophagus

Barrett’s is the replacement of the normal squamous oesophageal epithelium with a columnar phenotype and is the major precursor condition of the development of oesophageal adenocarcinoma. All patients with Barrett’s undergo routine and lifelong endoscopic surveillance to detect cancer but the majority of patients never progress to cancer. There are no effective predictive biomarkers for cancer risk and we believe this is because we do not fully understand the evolution to cancer in this condition. My lab has two major CRUK-funded programmes to study different aspects of the progression to cancer. 1)  Programme foundation awards to study the diversity of different Barrett’s oesophagus gland types and clonal evolution in the  progression to cancer and response to treatment to predict dysplasia risk and therapeutic response. 2) Grand Challenge: To investigate how the stromal reprogramming can prevent and revert inflammation-associated cancers (STORMing Cancer team with Prof Thea Tlsty, University of California San Francisco). Specifically, my lab will study how the stroma changes over time in Barrett’s particularly in patients the progress to cancer.

Stem cells

Epithelial tumours, namely carcinomas, are responsible for >90% of all human malignancies, and intuitively we believe that most, if not all carcinomas, have their origins in normal adult stem cells.

Despite a great deal of work in animals, we are still largely ignorant  about the nature and location of the stem cells in most epithelia. Thus, there is a great need for a robust technique to identify clonogenic cells and their  descendants, particularly in human tissues.

Our laboratory has developed methods to identify clonal  proliferative units in human epithelia, and we are now extending these studies to precisely identify the clonogenic cells, their location and nature (multipotential capacity), the cells that are the likely founders of  much premalignant disease. We are currently working on the stem cell dynamics of Barrett’s oesophagus using next generation bisulphite sequencing and in the human liver using mitochondrial next generation sequencing, developing molecular clock models to determine stem cell dynamics.

Other interests focus around;

• The cellular origins of Barrett’s oesophagus
• Field cancerisation of the human stomach
• Clonal expansion in ductal carcinoma in situ of the human breast

Other Activities

• Director, The Haemochromatosis Society
• Member, NCRI Upper GI group
• Member, The Amercian Gastroenterology Association
• Member, The New York Academy of Sciences
• Member, The Pathological Society of Great Britain and Ireland
• Gut, Journal scan review team
• Reviewer for Gut, J Pathol, Am J Gastroenterol, Stem Cells, Histopathology
• Reviewer for several funding bodies

Major Funding

• 2019- Cancer Research UK, Grand Challenge award, 'STORMing Cancer: STrOmal ReprograMing provides new directions to prevent and revert chronic inflammation-associated cancers,' share of £20m
• 2016-2021- Cancer Research UK, Foundation programme award, Investigating the role of gland phenotype in the evolution of Barrett’s oesophagus to dysplasia, ~£1.2m
• 2014-2017- CORE, Investigating clonal evolution in Barrett’s oesophagus, £210,000
• 2012- Barts Charity, Clonal expansion and progression of Ductal Carcinoma in situ to cancer in the human breast, £188,333

Recent Publications

Hepatocytes undergo punctuated expansion dynamics from a periportal stem cell niche in normal human liver. Passman AM, Haughey MJ, Carlotti E et al. J Hepatol (2023) (2)
https://www.ncbi.nlm.nih.gov/pubmed/37088309

Cell Competition in Carcinogenesis Madan E, Palma AM, Vudatha V et al. Cancer research (2022) 82(7) 4487-4496

THE IMMUNE CELL MICROENVIRONMENT IS DIFFERENTIALLY-ALTERED ACCORDING TO DIVERSE EPITHELIAL LANDSCAPES IN THE PROGRESSION TO CANCER IN BARRETT OESOPHAGUS Lin M-L, Hickey JW, Schurch CM et al. GASTROENTEROLOGY (2022) 162(11) S332-S332
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000826446201214&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=612ae0d773dcbdba3046f6df545e9f6a

Tu1165: THE IMMUNE CELL MICROENVIRONMENT IS DIFFERENTIALLY-ALTERED ACCORDING TO DIVERSE EPITHELIAL LANDSCAPES IN THE PROGRESSION TO CANCER IN BARRETT OESOPHAGUS Lin M-L, Hickey JW, Schürch CM et al. Gastroenterology (2022) 162(10) s-332

Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus Evans JA, Carlotti E, Lin ML et al. Gastroenterology (2022) 162(7) 1197-1209.e13

Evolutionary dynamics in Barrett oesophagus: implications for surveillance, risk stratification and therapy Schmidt M, Hackett RJ, Baker AM et al. Nature Reviews Gastroenterology and Hepatology (2022) 19(7) 95-111

Author Correction: Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis (Nature Cancer, (2020), 1, 10, (976-989), 10.1038/s43018-020-00112-5) Smith ALM, Whitehall JC, Bradshaw C et al. Nature Cancer (2021) 2(7) 129

Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis Smith ALM, Whitehall JC, Bradshaw C et al. Nature Cancer (2020) (1) 976-989

450 CLONAL DYNAMICS AND CELL-OF-ORIGIN OF NORMAL HEPATOCYTE EXPANSIONS IN HOMEOSTATIC HUMAN LIVERS AND THEIR ASSOCIATION WITH THE BILIARY EPITHELIUM Passman AM, Haughey MJ, Carlotti E et al. Gastroenterology (2020) 158(1) s-1276

CLONAL DYNAMICS AND CELL-OF-ORIGIN OF NORMAL HEPATOCYTE EXPANSIONS IN HOMEOSTATIC HUMAN LIVERS AND THEIR ASSOCIATION WITH THE BILIARY EPITHELIUM Passman AM, Haughey MJ, Carlotti E et al. GASTROENTEROLOGY (2020) 158(1) S1276-S1276
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000540349504191&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=612ae0d773dcbdba3046f6df545e9f6a

Team

Postdoctoral Researchers

• Dr Emanuela Carlotti
• Dr Adam Passman
• Dr Meng-Lay Lin

PhD Students

• Ms Viola Walther

Biography

After completing my PhD under Prof Tom MacDonald (ICMS), I spent several years researching inflammatory bowel disease and the immunology of infectious diseases of the gut. This eventually led me to work on stem cell biology within the human gastrointestinal tract with Professor Sir Nicholas Wright  and Professor Malcolm Alison. I re-joined Barts and the London in November 2008 and have developed my own research interests around the development of premalignant disease into cancer.