Abassi, L. | bioRxiv Science

bioRxiv2025

GLIS3 Marks a Neural-like Progenitor Cell State that Drives Metastasis in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a high rate of recurrence and metastasis despite intensive therapy. The neural-like progenitor (NRP) transcriptional program is enriched in residual disease after neoadjuvant chemotherapy and radiotherapy; however, the mechanisms for increased NRP expression in the post-treatment setting remain unclear. Here, we find that NRP signatures are strongly enriched in tissue injury and regeneration, and NRP cancer cells co-express transcription factors involved in pancreatic development. We identify both cell autonomous and ligand mediated mechanisms for inducing NRP expression in vitro. We establish and characterize isogenic mouse organoid overexpression models for transcription factors associated with the NRP, classical, and basal-like states. We discovered that Glis3 is a key NRP-associated transcription factor that drives malignant properties including greater clonogenicity, tumor growth, and metastasis compared to isogenic models for the classical and basal-like states. Our work highlights the emergence of clinically relevant developmental regeneration programs in the post-treatment context.

cancer biology↗

bioRxiv2020

SARS-CoV-2 Quasispecies Mediate Rapid Virus Evolution and Adaptation

Since the pandemic spread of SARS-CoV-2, the virus has exhibited remarkable genome stability, but recent emergence of novel variants show virus evolution potential. Here we show that SARS-CoV-2 rapidly adapts to Vero E6 cells that leads to loss of furin cleavage motif in spike protein. The adaptation is achieved by asymptotic expansion of minor virus subpopulations to dominant genotype, but wildtype sequence is maintained at low percentage in the virus swarm, and mediate reverse adaptation once the virus is passaged on human lung cells. The Vero E6-adapted virus show defected cell entry in human lung cells and the mutated spike variants cannot be processed by furin or TMPRSS2. However, the mutated S1/S2 site is cleaved by cathepsins with higher efficiency. Our data show that SARS-CoV-2 can rapidly adapt spike protein to available proteases and advocate for deep sequence surveillance to identify virus adaptation potential and novel variant emergence. Significance StatementRecently emerging SARS-CoV-2 variants B1.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor spike mutation and have been linked to increased virus pathogenesis. The emergence of these novel variants highlight coronavirus adaptation and evolution potential, despite the stable consensus genotype of clinical isolates. We show that subdominant variants maintained in the virus population enable the virus to rapidly adapt upon selection pressure. Although these adaptations lead to genotype change, the change is not absolute and genome with original genotype are maintained in virus swarm. Thus, our results imply that the relative stability of SARS-CoV-2 in numerous independent clinical isolates belies its potential for rapid adaptation to new conditions.

microbiology↗