Biology subjects

Lambert, D.

Publications and source records attributed to Lambert, D..

6 recordsLinked to original sources

bioRxiv2025

Multiple retinoic acid pathway factors function together during development of a mollusc

In developing chordate embryos, the retinoic acid (RA) pathway is involved in many key developmental patterning systems. Recently, it has become clear that at least some components of the RA pathway are more ancient than chordates. However, the participation of these components in an RA pathway, and the role of such a pathway in developing non-chordate embryos remain unclear. Here, we demonstrate the presence of an extensive set of RA pathway components in the genome of the mollusc Tritia obsoleta, and examine their expression using in situ hybridization. We then examined the function of multiple RA pathway genes using RA treatments, drug treatments and morpholino (MO) knockdowns. These manipulations impacted a similar set of structures in development, especially the shell and the digestive tract, indicating that the retinoic acid pathway is functional in Tritia. Together, this is the most comprehensive evidence yet for an RA signaling pathway functioning in embryogenesis of a non-chordate.

developmental biology↗

bioRxiv2025

Myosin VI orchestrates estrogen-driven gene expression in breast cancer cells.

Approximately 75% of breast cancer cases are estrogen receptor (ER)-positive, with endocrine therapies forming the foundation of treatment. However, therapeutic resistance remains a major clinical challenge, necessitating the identification of new molecular targets. Myosin VI (MVI), a motor protein increasingly linked to cancer, directly interacts with the ER and plays a key role in the spatial regulation of RNA Polymerase II. Notably, expression levels of MVI and ER are positively correlated across breast cancer tissues. Here, we present a multidisciplinary investigation combining advanced imaging, genomic profiling, and phenotypic characterisation to elucidate the interplay between MVI and the ER. We demonstrate that MVI nuclear localisation is dynamically regulated by estrogen signalling and ER activity. Conversely, ER nuclear localisation requires active MVI, suggesting a reciprocal regulatory mechanism. Furthermore, MVI influences subnuclear architecture, modulating ER transcriptional activity and downstream gene expression programmes that govern cell proliferation and migration. Importantly, pharmacological inhibition of MVI enhances the effect of hormone therapy, resulting in greater disruption of ER function than monotherapy alone. Moreover, MVI inhibition also suppresses the activity of hormone-resistant ER mutants, highlighting its potential to overcome therapy resistance. Our findings establish MVI as a critical regulator of ER nuclear dynamics and gene expression, supporting its candidacy as a novel therapeutic target in ER-positive breast cancer.

cancer biology↗

bioRxiv2025

A high-resolution genomic study of the Pama-Nyungan speaking Yolngu people of northeast Arnhem Land, Australia.

ObjectivesAbout 300 Aboriginal languages were spoken in Australia. These were classified into two groups: Pama-Nyungan (PN), comprised of one language Family, and Non-Pama-Nyungan (NPN) with more than 20 language Families. The Yolngu people belong to the larger PN Family and live in Arnhem Land in northern Australia. They are surrounded by groups who speak NPN languages. This study, using nuclear genomic and mitochondrial DNA data, was undertaken to shed light on the origins of the Yolngu people and their language. The nuclear genomic sequences of Yolngu people were compared to those of other Indigenous Australians, as well as Papuan, African, East Asian and European people. Materials and methodsWith the agreement of Indigenous participants, samples were collected from 13 Yolngu individuals and 4 people from neighbouring NPN speakers and their nuclear genomes sequenced to a 30lil coverage. Using the short-read DNA BGISEQ-500 technology, these sequences were mapped to a reference genome and identified [~]24.86 million Single Nucleotide Variants (SNVs). The Yolngu SNVs were then compared to those of 36 individuals from 10 other Indigenous populations/locations across Australia and four worldwide populations using multidimensional scaling, population structure, F3 statistics and phylogenetic analyses. ResultsUsing the above methods, we infer that Yolngu speakers are closely related to neighbouring NPN speakers, followed by the Weipa population. No European or East Asian admixture was detected in the genomes of the Yolngu speakers studied here, which contrasts with the genomes of many other PN speakers that have been studied. Our results show that Yolngu speakers are more closely related to other PN speakers in the northeast of Australia than to those in central and western Australia studied here. Yolngu and the other Australian populations from this study share Papuans as an out-group. DiscussionThe study presented here provides an account of the nuclear and mitochondrial genomic diversity within the PN Yolngu Aboriginal population. The results show the Yolngu sample and their NPN neighbours have a strong genetic relationship. They also offer evidence of ancestral links between the Yolngu and PN-speaking populations in Cape York. From earlier fingerprint studies, consistent with the genomic results shown here, we suggest that there was a movement of people from the east into northeast Arnhem Land, associated with the flooding of the Sahul Shelf, and that this occurred between about 11 Kya and 8 Kya ago. Several Yolngu myths point to such a movement. It is suggested that the spread of the PN language or its speakers may have influenced the population structure of the Yolngu. Further genomic studies, with larger samples, of populations to the east of the Yolngu around the Gulf of Carpentaria into Cape York are required to test this hypothesis. Our results imply that PN did not spread with the movement of people across the continent, rather, the PN languages diffused among the different populations. It seems clear that the languages dispersed and not the people. The low level of relatedness detected between the Yolngu people and the people of the central arid desert of Australia suggests a long period of separation with different patterns of migration. Beyond Australia, Yolngu are most closely related to the Papuan people of New Guinea.

genetics↗

bioRxiv2024

Investigation of cellular and molecular changes linked with neuropathic pain in healthy and injured human trigeminal nerves

Injuries to the trigeminal nerve, responsible for sensory innervation to the face, may occur during routine dental procedures, resulting in the formation of a neuroma accompanied by loss of sensation and/or symptoms of pain. In order to gain insight into the molecular mechanisms underpinning the sensory changes, single nuclei RNA sequencing and spatial transcriptomics were employed to profile the transcriptional landscape at single cell resolution of human trigeminal nerves and neuromas. Cellular and transcriptional changes were identified that correlated with the presence of pain, including an expansion of endothelial cells with a pro-inflammatory phenotype and over-expression of HLA-A, CXCL2 and CXCL8. Interactome analysis highlighted signalling changes linked with the presence of pain. HLA-A protein expression was confirmed in neuromas and positively correlated with symptoms of pain. The atlas generated represents a valuable resource for pain research, highlighting the role of inflammation, endothelial cell dysfunction and chemokine signalling in neuropathic pain.

neuroscience↗

bioRxiv2023

Cancer-associated fibroblast ADAM17 mediates a feed-forward loop promoting cancer cell migration

One of the ways in which cancer associated fibroblasts (CAF) influence the tumour-microenvironment (TME) is by releasing soluble factors to elicit responses in nearby cells. These factors may be released by modification of the extracellular matrix (ECM), secretion from intracellular compartments, or proteolytic cleavage from the cell surface. A major mediator of proteolytic processing of cell surface proteins is the a disintegrin and metalloproteinase (ADAM) family, commonly ADAM17. The role of ADAM17 in CAF, however, remains largely unknown. Here, we show that expression of ADAM17 was induced in normal oral fibroblasts (NOF) and CAF by exposure to oral cancer cell-derived conditioned medium and depletion of ADAM17 reduced the ability of CAF to promote cancer cell migration by negatively regulating cancer cell-associated N-cadherin. Proteomic analysis of ADAM17-depleted CAF revealed changes in the expression of pro-tumorigenic proteins, including fibroblast growth factor 2 (FGF2). Inhibition of FGF2/FGFR1 signalling abrogated the pro-migratory effects of CAF by reducing cancer cell-associated N-cadherin, an effect rescued by addition of recombinant FGF2. Taken together, these results indicate a novel molecular mechanism underpinning cancer cell migration in which tumour-derived factors induce ADAM17 expression in CAF, thus initiating a feed-forward loop wherein CAF release FGF2 to stimulate N-cadherin-dependent cancer cell migration.

cancer biology↗

bioRxiv2019

Mitogenomic Diversity in Sacred Ibis Mummies sheds light on early Egyptian practices

The ancient catacombs of Egypt harbor millions of well-preserved mummified Sacred Ibis (Threskiornis aethiopicus) dating from [~]600BC. Although it is known that a very large number of these votive mummies were sacrificed to the Egyptian God Thoth, how the ancient Egyptians obtained millions of these birds for mummification remains unresolved. Ancient Egyptian textual evidences suggest they may have been raised in dedicated large-scale farms. To investigate the most likely method used by the priests to secure birds for mummification, we report the first study of complete mitochondrial genomes of 14 Sacred Ibis mummies interred [~]2500 years ago. We analysed and compared the mitogenomic diversity among Sacred Ibis mummies to that found in modern Sacred Ibis populations from throughout Africa. The ancient birds show a high level of genetic variation comparable to that identified in modern African populations, contrary to the suggestion in ancient hieroglyphics (or ancient writings) of centralized industrial scale farming of sacrificial birds. This suggests a sustained short-term taming of the wild Sacred Ibis for the ritual yearly demand.

evolutionary biology↗