Cresswell, G. | Search bioRxiv

bioRxiv2021

Chronic CNS Pathology is Associated with Abnormal Collagen Deposition and Fibrotic-like Changes

Multiple sclerosis is a chronic debilitating disease of the CNS. The relapsing remitting form of the disease is driven by CNS directed inflammation. However, in the progressive forms of the disease, inflammation has abated and the underlying pathology is less well understood. In this paper, we show that chronic lesions in progressive MS are associated with fibrotic changes, a type of pathology that has previously not thought to occur in the CNS. In an animal model of chronic MS, late stage disease contains no inflammatory infiltrates and is instead characterized by collagen deposition that is histologically similar to fibrosis. In human MS samples, chronic, but not acute lesions, are devoid of inflammatory infiltrates and instead contain significant collagen deposition. Furthermore, we demonstrate that both mouse and human astrocytes are the cellular source of collagen. These results suggest that anti-fibrotic therapy may be beneficial in the treatment of progressive MS.

neuroscience↗

bioRxiv2020

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Aneuploidy, the loss and gain of whole and part chromosomes, is near-ubiquitous in cancer genomes and likely defines cancer cell biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterised. Here we perform longitudinal genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that represent distinct stages of tumour evolution through metastasis and treatment. Adenomas typically had few copy number alterations (CNAs) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual CRC glands from the same tumour typically had very similar karyotypes, despite evidence of ongoing instability at the cell level in patient tumours, cell lines and organoids. CNAs in metastatic lesions sampled from liver and other organs, after chemotherapy or targeted therapies, and in late recurrences were typically similar to the primary tumour. Mathematical modelling and statistical inference indicated that these data are consistent with the action of negative selection on CNAs that traps cancer cell genomes on a fitness peak defined by the specific pattern of chromosomal aberrations. These data suggest that the initial progression of colorectal cancer requires the traversal of a rugged fitness landscape and subsequent CNA evolution, including metastatic dissemination and therapeutic resistance, is constrained by negative selection.

cancer biology↗