Imaging and Molecular Annotation of Xenographs and Tumours (IMAXT): High throughput data and analysis infrastructure.

With the aim of producing a 3D representation of tumors, imaging and molecular annotation of xenografts and tumors (IMAXT) uses a large variety of modalities in order to acquire tumor samples and produce a map of every cell in the tumor and its host environment. With the large volume and variety of data produced in the project, we developed automatic data workflows and analysis pipelines. We introduce a research methodology where scientists connect to a cloud environment to perform analysis close to where data are located, instead of bringing data to their local computers. Here, we present the data and analysis infrastructure, discuss the unique computational challenges and describe the analysis chains developed and deployed to generate molecularly annotated tumor models. Registration is achieved by use of a novel technique involving spherical fiducial marks that are visible in all imaging modalities used within IMAXT. The automatic pipelines are highly optimized and allow to obtain processed datasets several times quicker than current solutions narrowing the gap between data acquisition and scientific exploitation.

Journal Biological Imaging
Authors Eduardo A. González-Solares et al
DATE 14 April 2023
Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1,2,3,4,5,6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett’s oesophagus. These data included 206 biopsies in Barrett’s oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case–control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett’s-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

Team eDyNAmiC
Journal Nature
Authors Jens Luebeck et al
DATE 12 April 2023
Impact of the COVID-19 pandemic in the early-onset colorectal cancer

The COVID19 pandemic has affected the spectrum of cancer care worldwide. Early onset colorectal cancer (EOCRC) is defined as diagnosis below the age of 50. Patients with EOCRC faced multiple challenges during the COVID19 pandemic and in some institutions it jeopardized cancer diagnosis and care delivery. Our study aims to identify the clinicopathological features and outcomes of patients with EOCRC in our Centre during the first wave of the pandemic in comparison with the same period in 2019 and 2021.

Patients with EOCRC visited for the first time at Vall d'Hebron University Hospital in Spain from the 1st March to 31st August of 2019, 2020 and 2021 were included in the analysis. 177 patients with EOCRC were visited for the first time between 2019 and 2021, of which 90 patients met the inclusion criteria (2019: 30 patients, 2020: 29 patients, 2021: 31 patients). Neither differences in frequency nor in stage at diagnosis or at first visit during the given periods were observed. Of note, indication of systemic therapy in the adjuvant or metastatic setting was not altered. Days to treatment initiation and enrollment in clinical trials in this subpopulation was not affected due to the COVID-19 outbreak.

Journal Translational Oncology
Authors Iosune Baraibar et al
DATE 05 April 2023
A common cancer at an uncommon age

Early-onset colorectal cancer (EOCRC), also called young-onset colorectal cancer, is defined as CRC diagnosed in individuals aged less than 50 years. EOCRC is increasing globally and anticipated to become the leading cause of cancer death in individuals aged 20 to 49 in the US by 2030 (1). Since the 1990s, the age-adjusted incidence of EOCRC has risen at an alarming rate of 2 to 4% per year in many countries, with even sharper increases in individuals younger than 30 years (1). This is despite a reduction in overall CRC incidence that is likely attributable to improved screening and prevention in older individuals. The exact reasons and pathophysiology behind the rising incidence of EOCRC remain unknown. Currently, only limited studies exist and they have focused on single aspects of EOCRC etiology. A multidisciplinary path forward is needed to expand the understanding of this increasingly prevalent problem.

Journal Science Magazine
Authors Marios Giannakis, Kimmie Ng
DATE 16 March 2023
Epithelial-Stromal Interactions in Barrett’s Esophagus Modeled in Human Organ Chips

Barrett’s esophagus (BE) is an adaptive response of the lower esophagus to recurring exposure to gastroesophageal reflux that leads to intestinal metaplasia and/or gastric metaplasia depending on the specific criteria in each country.1 The tissue microenvironment and local resident fibroblasts are critically involved in tissue homeostasis and repair processes2; however, the involvement of stromal-derived fibroblasts in BE and, in particular, their involvement in rare instances of metaplastic transformation and progression to esophageal adenocarcinoma (EAC) are poorly understood. To examine this, we have leveraged a human organ-on-a-chip (Organ Chip) microfluidic culture methodology3 to construct tissue recombinant models containing esophageal epithelial cells isolated from organoids derived from multiple BE patients (Figure A1A and B and Table) interfaced with fibroblasts isolated from normal esophagus or from metaplastic, dysplastic, or cancerous regions of the same esophagus that was surgically resected from an EAC patient. Flow cytometric analysis confirmed that 80–95% of the stromal cells isolated from each of these regions stained positively for 2 different known fibroblast markers (CD90 and CD73), and that were regional differences as well as some interpatient variability in the expression of fibroblast surface markers, including CD36, podoplanin, platelet-derived growth factor-α, and platelet-derived growth factor-β (Figure A2A and B). Interestingly, this analysis also revealed that fibroblasts from a healthy, disease-free esophagus exhibited a distinct phenotype that those from adjacent normal-appearing regions from EAC patients. In contrast to a past in vitro BE modeling study,4 all cell derivatives used in these chips were not genetically manipulated and their growth conditions were designed to retain the natural self-renewing property of the BE tissue which is believed to arise from esophageal or gastric glandular epithelium,5,6,7 rather than using conditions optimized for growth of normal squamous epithelium. This is the first time, to our knowledge, that it has been possible to analyze in vitro the heterogeneous responses of BE epithelium to coculture with stromal cells from different regions of the same organ from the same patient that exhibit differences in disease phenotype in vivo.

Team STORMing Cancer
Journal Gastro Hep Advances
Authors Elee Shimshoni et al
DATE 08 March 2023