Pietras, K. | bioRxiv Science

bioRxiv2022

Inherent evolutionary unpredictability in cancer model system

Despite the advent of personalized medicine, it is still difficult to predict how a cancer develops over time at the level of the individual patient or even in cancer model systems which begs the question whether certain aspects of cancer can ever be predicted or if there is an inherent unpredictability in cancer, similar to other complex biological systems, We demonstrate by a combination of agent-based mathematical modelling and analysis of data from patient-derived xenograft systems from multiple cancer types that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer cells. Our findings indicate that under those conditions, the cancer genome behaves as a complex dynamic system, making its long-term evolution inherently unpredictable.

evolutionary biology↗

bioRxiv2021

Infection of brain pericytes underlying neuropathology of COVID-19 patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFR{beta} in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

pathology↗