Biology subjects

Khaled, W.

Publications and source records attributed to Khaled, W..

6 recordsLinked to original sources

bioRxiv2026

Combinatorial screening of biological degrader modules identifies heterobifunctional molecules that efficiently destroy MYC, leading to rapid tumour cell death in vitro and in vivo

Targeted protein degradation is a potent strategy against intracellular proteins impervious to traditional drugs. We describe a platform reliant on high-throughput cloning and mRNA-based delivery to quickly screen 100s-1000s of modular biological degraders, which we challenge against the high-turnover c-Myc oncoprotein. We uncover critical principles to drive degrader discovery against any target, free from tagging or prior cell line engineering, with direct applications in research and potentially therapy. We demonstrate the feasibility of targeted protein degradation of c-Myc across in vitro cancer models and in vivo xenograft model, uncovering distinct cellular responses between c-Myc degradation and inhibition.

bioengineering↗

bioRxiv2023

An interactive cellular ecosystem blocks epithelial transformation in naked mole-rat

Long-lived species suppress cancer despite accumulating somatic mutations throughout life, but how this is achieved in renewing tissues remains unclear. Here, we show that naked mole-rat skin uncouples high cellular turnover from cancer risk through coordinated epithelial and stromal mechanisms that constrain clonal outgrowth and suppress tumor-promoting inflammation. Despite elevated epidermal proliferation and mutational burden, naked mole-rat skin maintains tissue integrity through an expanded pool of early committed progenitor (hybrid) cells and replication-coupled genome maintenance pathways. Under chronic carcinogenic stress, undifferentiated basal cells replenish the hybrid progenitor pool. This dilutes initiated clones and permits only limited selective expansion of rare cancer gene-mutant clones. Depletion of the hybrid compartment shifts this protective state toward clonal expansion and inflammatory activation. These expanding clones are further constrained by a highly tumor-suppressive stromal microenvironment, driven by fibroblasts that adopt a metabolically restricted, non-inflammatory program. Together, our data uncover a multi-layered tumor-suppressive strategy that couples turnover-driven regeneration with an anti-permissive stromal niche to prevent malignant progression under mutagenic stress.

cancer biology↗

bioRxiv2023

An autochthonous model of lung cancer in the Naked Mole-Rat (Heterocephalus glaber)

Studies on cancer resistance in the naked mole-rat (NMR) have generally failed to interrogate possible resistance mechanisms in a physiological context. Here, we provide evidence that the NMR presents as a novel model of tumor initiation. We developed an endogenous lung cancer model in NMRs, driven by an oncogenic Eml4-Alk fusion protein introduced through CRISPR- mediated genome editing. While this is sufficient to drive tumorigenesis in mice, the development of progressive disease in NMRs required the additional loss of key tumor suppressors. Our results show that tumor initiation in NMRs more closely recapitulates that of human tumors. This suggests that the proposed "resistance" of NMRs to cancer development may stem from tumor initiation events that are likely to be comparable to the mechanisms in human cells. One-Sentence SummaryTumor development in the cancer-resistant naked mole-rat more accurately represents the tumor initiation process in humans.

cancer biology↗

bioRxiv2020

Transcriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk

Findings from epidemiological studies suggest that breast cancer risk is influenced by parity in an age-dependent manner. However, human mammary tissue remodelling that takes place during pregnancy and lactation remain little understood due to the challenge of acquiring samples. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk compared to resting, non-lactating breast tissue. Thereby, we determined that separate to breast tissue, human milk largely contains epithelial cells belonging to the luminal lineage, as well as immune cells. Our data reveal the presence of two distinct secretory luminal cell clusters in milk which highly express luminal progenitor signatures akin to non-lactating breast tissue luminal cells. Taking advantage of the fact that both the resting and lactating mammary gland contain a luminal compartment, we focussed on comparing these transcriptomes and identified differences in mammary cell function and metabolism between these maturation states. These findings provide the basis to dissect human luminal differentiation and milk biosynthesis pathways that in the future, may be interrogated to determine how parity influences luminal cell metabolism and breast cancer risk.

cell biology↗

bioRxiv2018

Naked mole rat hyaluronan - an extreme folding biopolymer

Hyaluronan (HA) is a key component of the extracellular matrix. Given the fundamental role of HA in the cancer resistance of the naked mole-rat (NMR), we undertook to explore the structural and soft matter properties of this species-specific variant, a necessary step for its development as a biomaterial. We examined HA extracted from NMR brain, lung, and skin, as well as that isolated from the medium of immortalised cells. In common with mouse HA, NMR HA forms a range of assemblies corresponding to a wide distribution of molecular weights. However, unique to the NMR, are highly folded structures, whose characteristic morphology is dependent on the tissue type. Skin HA forms tightly packed assemblies that have spring-like mechanical properties in addition to a strong affinity for water. Brain HA forms three dimensional folded structures similar to the macroscopic appearance of the gyri and sulci of the human brain. Lung HA forms an impenetrable mesh of interwoven folds in a morphology that can only be described as resembling a snowman. Unlike HA that is commercially available, NMR HA readily forms robust gels without the need for chemical cross-linking contrasting. NMR HA gels sharply transition from viscoelastic to elastic like properties upon dehydration or repeated loading. In addition, NMR HA can form ordered thin films with an underlying semi-crystalline structure. Given the role of HA in maintaining hydration in the skin it is plausible that the folded structures contribute to both the elasticity and youthfulness of NMR skin. It is also possible that such densely folded materials could present a considerable barrier to cell invasion throughout the tissues, a useful characteristic for a biomaterial.

biophysics↗

bioRxiv2018

Naked Mole-Rat Cells are Susceptible to Malignant Transformation by SV40LT and Oncogenic Ras

The Naked Mole-Rat, Hetercephalus glaber, is a mouse-sized subterranean rodent native to East Africa. Research on NMRs is intensifying in an effort to gain leverage from their unusual physiology, long-life span and cancer resistance. Few studies have attempted to explain the reasons behind NMRs cancer resistance, but most prominently Tian et al. reported that NMR cells produce high-molecular weight hyaluronan as a potential cause for the NMRs cancer resistance. Tian et al. have shown that NMR cells are resistant to transformation by SV40 Large T Antigen (SV40LT) and oncogenic HRAS (HRASG12V), a combination of oncogenes sufficient to transform mouse and rat fibroblasts. We have developed a single lentiviral vector to deliver both these oncogenes and generated multiple cell lines from five different tissues and nine different NMRs, and report here that contrary to Tian et al.s observation, NMR cells are susceptible to oncogenic transformation by SV40LT and HRAS. Our data thus point to a non-cell autonomous mechanism underlying the remarkable cancer resistance of NMRs. Identifying these non-cell autonomous mechanisms could have implications on our understanding of human cancer development.

cancer biology↗