Biology subjects

McLennan, R.

Publications and source records attributed to McLennan, R..

4 recordsLinked to original sources

bioRxiv2023

Targeting cancer with small molecule pan-KRAS degraders

Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue (1). However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand (2). Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. One-Sentence SummaryThe most prevalent KRAS variants which drive tumour growth in a major share of cancer patients can be targeted with a single small molecule degrader.

pharmacology and toxicology↗

bioRxiv2020

Transcriptome profiling of the branchial arches reveals cell type composition and a conserved signature of neural crest cell invasion

The vertebrate branchial arches that give rise to structures of the head, neck, and heart form with very dynamic tissue growth and well-choreographed neural crest, ectoderm, and mesoderm cell dynamics. Although this morphogenesis has been studied by marker expression and fate-mapping, the mechanisms that control the collective migration and diversity of the neural crest and surrounding tissues remain unclear, in part due to the effects of averaging and need for cell isolation in conventional transcriptome analysis experiments of multiple cell populations. We used label free single cell RNA sequencing on 95,000 individual cells at 2 developmental stages encompassing formation of the first four chick branchial arches to measure the transcriptional states that define the cellular hierarchy and invasion signature of the migrating neural crest. The results confirmed basic features of cell type diversity and led to the discovery of many novel markers that discriminate between axial level and distal-to-proximal cell populations within the branchial arches and neural crest streams. We identified the transcriptional signature of the most invasive neural crest that is conserved within each branchial arch stream and elucidated a set of genes common to other cell invasion signatures in types in cancer, wound healing and development. These data robustly delineate molecularly distinct cell types within the branchial arches and identify important molecular transitions within the migrating neural crest during development.

developmental biology↗

bioRxiv2019

Head Mesoderm Tissue Growth, Dynamics and Neural Crest Cell Migration

Vertebrate head morphogenesis involves orchestrated cell growth and tissue movements of the mesoderm and neural crest to form the distinct craniofacial pattern. To better understand structural birth defects, it is important that we learn how these processes are controlled. Here, we examine this question during chick head morphogenesis using time-lapse imaging, computational modeling, and experiment. We find that head mesodermal cells are inherently dynamic in culture and alter cell behaviors in the presence of either ectoderm or neural crest cells. Mesodermal cells in vivo display large-scale whirling motions that rapidly transition to lateral, directed movements after neural crest cells emerge. Computer model simulations predict distinct changes in neural crest migration as the spatio-temporal growth profile of the mesoderm is varied. BrdU-labeling and photoconversion combined with cell density measurements then reveal non-uniform mesoderm growth in space and time. Chemical inhibition of head mesoderm proliferation or ablation of premigratory neural crest alters mesoderm growth and neural crest migration, implying a dynamic feedback between tissue growth and neural crest cell signaling to confer robustness to the system.\n\nSummary StatementDynamic feedback between tissue growth and neural crest cell migration ensures robust neural crest stream formation and head morphogenesis shown by time-lapse microscopy, mathematical modeling and embryo perturbations.

developmental biology↗

bioRxiv2019

Neural crest cells bulldoze through the microenvironment using Aquaporin-1 to stabilize filopodia

Neural crest migration requires cells to move through an environment filled with dense extracellular matrix and mesoderm to reach targets throughout the vertebrate embryo. Here, we use high-resolution microscopy, computational modeling, and in vitro and in vivo cell invasion assays to investigate the function of Aquaporin-1 (AQP-1) signaling. We find that migrating lead cranial neural crest cells express AQP-1 mRNA and protein, implicating a biological role for water channel protein function during invasion. Differential AQP-1 levels affect neural crest cell speed, direction, and the length and stability of cell filopodia. Further, AQP-1 enhances matrix metalloprotease (MMP) activity and colocalizes with phosphorylated focal adhesion kinases (pFAK). Co-localization of AQP-1 expression with EphB guidance receptors in the same migrating neural crest cells raises novel implications for the concept of guided bulldozing by lead cells during migration.

developmental biology↗