Our research focuses on stem cell niches and clonal expansion in Barrett’s oesophagus, stomach and breast cancer.
Crypt fusion as a homeostatic mechanism in the human colon. In press Gut.
Analysis of clonal expansions through the normal and premalignant human breast epithelium reveals the presence of luminal stem cells. J Pathol (2018) 244(10):61-70. PMID: 28940516
The stem cell organisation, and the proliferative and gene expression profile of Barrett’s epithelium, replicates pyloric-type gastric glands. Gut (2014) 63(12):1854-63. PMID: 24550372
Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut (2011) 61(10):1380-9. PMID: 22200839
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.
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;
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
Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer Cross W, Mossner M, Nowinski S et al. (2020) (18)
MLH1 deficiency leads to deregulated mitochondrial metabolism Martin S Cell Death and Disease (2019) 10(1) 795-795
The Cell of Origin of Normal Human Hepatocytes has a Common Ancestor with Biliary Epithelium and Hepatocyte Clonal Expansions Arise from the Portal Tract and Drift to the Central Vein Passman A, Williams M, Carlotti E et al. JOURNAL OF PATHOLOGY (2019) 249(11) S16-S16
Evolutionary history of human colitis-associated colorectal cancer Baker AM, Cross W, Curtius K et al. Gut (2019) 68(7) 985-995
PTU-105 Automated, algorithm based extraction of Barrett’s surveillance metrics from natural language text is reliable Zeki S, Hackett R, Dunn J et al. Gut (2019) 68(10) a243
Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon. Baker A-M, Cereser B, Melton S et al. Cell Rep (2019) 27(1) 2524-2524
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.