Premetastatic lymph node niche

Microbiota at the tumour site

HORMAD1 as a driver of genomic instability

Evolution of the premetastatic lymph node niche

The presence of lymph node (LN) metastasis is one of the most important prognostic factors in breast and many other cancers, and the overall survival decreases as the number of cancerous (involved) LNs increases. Despite, a subset of these patients respond well to treatment and achieve long-term survival.  Most commonly, regional LNs are excised, histopathologically processed and examined by a pathologist, to determine if LNs harbour cancerous cells.  Although tumour cell metastasis is often preceded by alterations in the microenvironment of the metastatic organ in preparation for the arrival of and an effective colonisation by malignant cells, little attention is given to cancer-free (uninvolved) LNs and the progression from an uninvolved LN to an involved LN. In collaboration with Professors Tony Ng, Professor Sarah Pinder and Professor Ton Coolen, we were the first to report on morphological changes in the uninvolved LNs, being risk predictive of developing distant metastasis and are now elucidating the underlying biological and translational relevance of the pre-metastatic LNs.

The microbiota at the tumour site

The presence of the microbiota at the tumour site influences the transcriptional and genomic landscape of cancers. Fusobacterium nucleatum is one example of a highly abundant bacterial species found in the tumour microenvironment of several cancers including, colorectal, breast, pancreatic and oral. In collaboration with the Translational Systems Biology group lead by Saeed Shoaie we are now implementing computational methods to detect the presence of Fusobacterium nucleatum in largescale publicly available data sets to understand how the tumour microbiome influences downstream interactions in the immune microenvironment and genomic instability in the cancer genome.

HORMAD1 as a genomic instability driver

Triple-negative breast cancers (TNBCs) are characterised by extensive inter- and intra-tumoural heterogeneity, encompass   clinically   and   biologically   distinct subgroups, display a diverse landscape of immune cell infiltrates, and are driven by a spectrum of genomic alterations. This complexity provides a real challenge for patient management. As part of the Breast Cancer Now Research Unit at King’s College London, we identified HORMAD1, a Cancer/Testis (CT) antigen, as a driver of genomic instability in TNBC.CT antigens are well-known for their immunogenic capabilities and a relatively small subset of these antigens also play an essential role in meiosis. However, their ectopic expression in cancer cells and the ramifications on DNA damage response are less well understood.

Sequence patterns and dynamics of genomic instability

Our previous research found HORMAD1 is highly associated with allelic-imbalanced copy number alterations. Chang is investigating the spatial localisation of HORMAD1 induced genomic instability in isogenic cell line models using whole-genome sequencing and ChIP-sequencing data. Sequence patterns (DNA  motifs) and dynamics (secondary DNA structures), carry valuable information of underlying DNA damage repair mechanisms and contribute to our understanding of HORMAD1 in cancer cells.

Immunobiology and DNA damage response in triple-negative breast cancer

In this project, Jelmar seeks to understand both the immunobiology and DNA damage responses of HORMAD1 by interrogating multi-omics data from primary TNBCs. While the genomic landscape provides valuable information of on-going and historical   mutagenic   processes, transcriptional   programs   give   insight   into compensatory processes required to maintain cell viability and can be used to interrogate the tumour immune microenvironment. By incorporating these diverse features using unsupervised machine learning approaches, patients can be stratified by both immunobiology and DNA damage response. Based on biological features, patient subgroups can be investigated retrospectively in clinical trials with regards to appropriate treatment response

Identifying   molecular   correlates   by   systematic   PanCancer analysis

Preliminary analyses indicated the ectopic expression of HORMAD1 is not restricted to TNBCs. Yue is performing a systematic PanCancer analysis of HORMAD1 expression to identify in which tumour types HORMAD1 is expressed. He seeks to further decipher links between molecular correlates, such as genomic instability and immune infiltrates, in each of these tumour types to further our understanding of the role of HORMAD1 in cancer cells.