Biology subjects

Alham, N. K.

Publications and source records attributed to Alham, N. K..

3 recordsLinked to original sources

bioRxiv2026

Scalable spatial DNA sequencing from archival tissue maps copy number subclones

Spatially resolved DNA sequencing holds promise due to its potential utility in understanding cancer intra-tumour heterogeneity and tumour evolution in relation to tissue architecture. However, it has so far been used to a limited extent due to technical challenges and high cost of existing methods. Hence we aimed to develop a high throughput spatial genomic assay to obtain copy number alteration (CNA) information at user-defined spatial resolution. We derived CNA profiles from ultra-low coverage whole genome sequencing at sub-millimetre resolution from archival samples using a novel method called Adaptive Resolution Multiscale Spatial DNA sequencing (ARMS DNAseq). We used it to profile CNAs from more than 766 regions (tiles) from 3 patients, covering a total area of over 300 mm2, with 1.2-2.6 million mapped reads per tile and tile sizes of 0.1-0.99mm2. Using ARMS DNAseq, we delineate tumour evolution in a spatial context, and identify more tumour subclones that were obscured or incompletely represented in bulk multi-region whole genome sequencing. Next, we show associations between tumour subclones and morphology, and prediction of subclone identity from deep learning-derived image representations. Finally, we demonstrate multi-omic integration by alignment with spatial transcriptomic data, showing subclone-specific immune cell co-occurrence as well as transcriptional programmes cutting across subclone boundaries. ARMS DNAseq converts low-throughput, region-by-region profiling into a scalable and adaptable workflow for direct spatial copy number profiling from archival tissue sections.

genomics↗

bioRxiv2025

Wnt-dependent spatiotemporal reprogramming ofbone marrow niches drives fibrosis

Bone marrow fibrosis is the most extensive matrix remodeling of the microenvironment and can include de novo formation of bone (osteosclerosis). Spatiotemporal information on the contribution of distinct bone marrow niche populations to this process is incomplete. We demonstrate that fibrosis-inducing hematopoietic cells cause profibrotic reprogramming of perivascular CXCL12 abundant reticular (CAR) progenitor cells resulting in loss of their hematopoiesis-support and upregulation of osteogenic and pro-apoptotic programs. In turn, peritrabecular osteolineage cells (OLCs) are activated in an injury-specific, Wnt-dependent manner, comparable to skeletal repair. OLCs fuel bone marrow fibrosis through their expansion and skewed differentiation, resulting in osteosclerosis and expansion of Ly6a+ fibroblasts. NCAM1 expression marks peritrabecular OLCs and their expansion into the central marrow is specific for fibrosis in mice and patients. Peritrabecular stromal b-catenin expression is linked to fibrosis in patients and inhibition of Wnt signaling reduces bone marrow fibrosis and osteosclerosis, possibly being a clinically relevant therapeutic target.

molecular biology↗

bioRxiv2023

Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole genome sequencing with histopathological features

Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The emergence and evolution of cancer clones at this early stage of expansion and spread has not been studied in detail. We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes. Based on these data, we delineated the route of tumour progression and metastasis following the transformation of adenocarcinoma to amphicrine morphology, the molecular events leading to whole genome duplication associated with a single clonal expansion and identified putative driver events associated with local invasion and lymph node metastasis. We also correlated genomic changes associated with differences in morphology and identified putative driver events associated with spread to seminal vesicle invasion and lymph node metastasis. Taken together, these findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes associated with morphological transformation. Our results demonstrate the value of integrating multi-region sequencing with histopathological data to study tumour evolution and identify mechanisms of prostate cancer spread.

cancer biology↗