Biology subjects

Ridley, A.

Publications and source records attributed to Ridley, A..

5 recordsLinked to original sources

bioRxiv2024

Key Regulatory Elements of the TGFbeta-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types

Transforming growth factor-beta (TGF{beta}) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGF{beta} have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGF{beta}-regulated antigen expressed by mesenchymal-derived cancer cells and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGF{beta}-driven LRRC15+ CAFs increased tumor infiltration of CD8+ T cells. However, the underlying pathobiological mechanisms prompting TGF{beta}s upregulation of LRRC15 expression are unclear. Using an integrated approach combining functional compound screening with single-cell RNA sequencing, we reveal key genomic features regulating TGF{beta}s ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes--MMP2, SPARC, TGF{beta}R2, and WNT5B--central to TGF{beta}-induced LRRC15 pathobiology. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing co-treatment options.

pharmacology and toxicology↗

bioRxiv2024

Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. We have developed a humanized monoclonal antibody (mAb), DUNP19, that specifically binds to a phylogenetically conserved LRRC15 epitope and is internalized by target-expressing cancer and stromal cells. In xenograft mouse models, Lutetium-177 labeled DUNP19 ([177Lu]-DUNP19) enables non-invasive imaging and precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts (CAFs), halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [177Lu]-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a transforming growth factor beta (TGF{beta})-driven and LRRC15+ signature associated with immunotherapy resistance. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and aggressive disease. SIGNIFICANCEWe introduce a pioneering LRRC15-guided radio-theranostic approach integrating clinical imaging and radioimmunotherapy. Our strategy utilizes a mAb, DUNP19, to target LRRC15-expressing cancer cells and fibroblasts, demonstrating significant tumor reduction, prolonged survival, and reversal of TGF{beta}-driven treatment resistance. This approach offers a promising strategy for improving outcomes in aggressive cancers.

pharmacology and toxicology↗

bioRxiv2023

The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis

RNA-binding proteins (RBPs) are emerging as important regulators of pathogenesis, including cancer. Here we reveal that the recently characterised RBPs LARP4A and LARP4B are differentially overexpressed in primary osteosarcoma and osteosarcoma lung metastases, as well as in prostate cancer. Depletion of LARP4A and LARP4B inhibited primary tumour growth and metastatic spread in xenograft studies, as well as inhibiting cell proliferation, motility and migration. Transcriptomic profiling combined with high content multiparametric cell cycle analysis unveiled a central role for LARP4B, but not LARP4A, in regulating cell cycle progression in osteosarcoma and prostate cancer cell lines, potentially through modulating the post-transcriptional regulation of RNA targets that include key cell cycle proteins such as Cyclins B1 and E2, Aurora B and E2F1. Our work assigns new functions to LARP4A and LARP4B as pro-tumorigenic proteins in bone and prostate cancer, highlights their similarities while indicating distinct functional aspects, and adds significantly to the rapidly increasing roles of RBPs in different cancer models. Uncovering clear biological roles for these paralogous proteins provides new avenues for identifying novel tissue-specific targets and potential druggable intervention.

cancer biology↗

bioRxiv2022

A comparative study of two grasswren species reveals strong genetic divergence between a peninsula and mainland population

Dispersal patterns dictate genetic population structure, and ultimately population resilience, through maintaining critical ecological processes and genetic diversity. Direct observation of dispersal events is not often possible, but genetic methods offer an alternative method of indirectly measuring dispersal. Here, we use 7 652 genome-wide single-nucleotide polymorphisms (SNPs) to evaluate genetic population structure and infer dispersal capabilities of the Western Grasswren (Amytornis textilis textilis; WGW) in Western Australia (n = 118), utilising a sister species, the Thick-billed Grasswren (Amytornis modestus; TBGW) as a comparison dataset (n = 80). We found genetic divergence and low genetic diversity between two populations (Hamelin and Peron) in the WGW, despite evidence of long dispersal distances within populations by females. In addition, the two WGW populations were found to be more genetically divergent than two described subspecies of TBGW, despite the WGW occurring over a smaller spatial scale. By comparing these two grasswren species, our data suggest a narrow strip of land may be acting as a geographic barrier in the WGW, limiting dispersal between a peninsula population to the mainland. We investigate if morphology aligns with genetic divergence, with some estimates of divergence between WGW populations greater than those between subspecies of TBGW. However, confidence intervals were large, preventing definitive conclusions. Our results support the hypothesis that peninsula populations of small, ground-dwelling birds are genetically isolated from adjacent mainland populations. Furthermore, there is evidence to suggest that the limited gene flow is asymmetrical, with directional dispersal occurring from the bounded peninsula population to the mainland. Our study also highlights how substantial genetic divergence does not necessarily coincide with phenotypic differences.

genetics↗

bioRxiv2021

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates

Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.

immunology↗