Biology subjects

Powell, C. J.

Publications and source records attributed to Powell, C. J..

5 recordsLinked to original sources

bioRxiv2026

Engineered T cells controlled by granulocyte colony-stimulating factor eradicate murine melanoma without lymphodepletion or interleukin-2

Tumour-infiltrating lymphocyte (TIL) therapy can be effective against metastatic melanoma, including immune checkpoint-resistant disease, but current protocols require lymphodepletion and high-dose interleukin-2 (IL-2), which can cause substantial toxicity. To overcome this limitation, we engineered a chimeric receptor, G2R, that generates an IL-2-like proliferative signal in response to granulocyte colony-stimulating factor (G-CSF), a well-tolerated cytokine widely used in oncology. Human T cells expressing G2R expanded in vitro in response to G-CSF in place of IL-2 or interleukin-15 (IL-15), and the three cytokines induced broadly similar intracellular signalling and cytokine secretion profiles. In immune-competent mice bearing established B16-F10 melanoma, adoptive transfer of G2R-expressing, tumour-reactive CD8+ T cells followed by systemic G-CSF treatment induced profound T cell expansion. This was accompanied by complete, durable tumour regression in over 75% of animals without the need for lymphodepletion, exogenous IL-2 or any other therapy. G-CSF treatment induced transient neutrophil expansion in peripheral blood but no increase in intratumoural neutrophils or macrophages. G2R-expressing memory T cells persisted long-term and could be re-expanded upon G-CSF re-treatment, enabling rejection of second tumour challenges. Thus, G-CSF can be repurposed to enable clinician-controlled anti-tumour T cell responses of profound magnitude, efficacy and durability, an approach that is readily translatable to humans.

immunology↗

bioRxiv2025

Pancreatic injury induces β-cell regeneration in axolotl

BackgroundDiabetes is a condition characterized by a loss of pancreatic {beta}-cell function which results in the dysregulation of insulin homeostasis. Using a partial pancreatectomy model in axolotl, we aimed to observe the pancreatic response to injury. ResultsHere we show a comprehensive histological assessment of pancreatic islets in axolotl. Following pancreatic injury, no apparent blastemal structure was observed. We found a significant, organ-wide increase in cellular proliferation post-resection in the pancreas compared to sham-operated controls. This proliferative response was most robust at the site of injury. We found that {beta}-cells actively contributed to the increased rates of proliferation upon injury. {beta}-cell proliferation manifested in increased {beta}-cell mass in injured tissue at two weeks post injury. At four weeks post injury, we found organ-wide proliferation to be extinguished while proliferation at the injury site persisted, corresponding to pancreatic tissue recovery. Similarly, total {beta}-cell mass was comparable to sham after four weeks. ConclusionsOur findings suggest a non-blastema-mediated regeneration process takes place in the pancreas, by which pancreatic resection induces whole-organ {beta}-cell proliferation without the formation of a blastemal structure. This process is analogous to other models of compensatory growth in axolotl, including liver regeneration.

developmental biology↗

bioRxiv2024

An evolutionarily conserved role for VEGF signaling in the expansion of non-vascular tissue during regeneration.

Salamanders are capable of regenerating whole limbs throughout life, a feat that is unmatched within tetrapods. Limb regeneration is dependent upon the formation of a blastema, which contains undifferentiated cells capable of giving rise to most cells of the regenerated limb. Innervation is required for regeneration, along with many signaling pathways, including FGF, BMP and Wnt, but the role of VEGF signaling during salamander limb regeneration is not well understood. Here we show that VEGF signaling is essential for limb regeneration and that blastema cells and limb fibroblasts display impaired proliferation in the absence of VEGF signaling. By performing analogous experiments in planaria, which lack vasculature, we show a potential evolutionarily conserved role for VEGF in the expansion of blastema tissues that is separable from angiogenesis. Moreover, loss of VEGF signaling reduces induction of EMT-like processes, suggesting VEGF signaling functions upstream of the expression of EMT transcription factors, including Snai2. These findings highlight potential roles for VEGF signaling during regeneration which may extend beyond typical findings related to angiogenesis.

developmental biology↗

bioRxiv2024

Amputation Triggers Long-Range Epidermal Permeability Changes in Evolutionarily Distant Regenerative Organisms

Previous studies have reported that amputation invokes body-wide responses in regenerative organisms, but most have not examined the implications of these changes beyond the region of tissue regrowth. Specifically, long-range epidermal responses to amputation are largely uncharacterized, with research on amputation-induced epidermal responses in regenerative organisms traditionally being restricted to the wound site. Here, we investigate the effect of amputation on long-range epidermal permeability in two evolutionarily distant, regenerative organisms: axolotls and planarians. We find that amputation triggers a long-range increase in epidermal permeability in axolotls, accompanied by a long-range epidermal downregulation in MAPK signaling. Additionally, we provide functional evidence that pharmacologically inhibiting MAPK signaling in regenerating planarians increases long-range epidermal permeability. These findings advance our knowledge of body-wide changes due to amputation in regenerative organisms and warrant further study on whether epidermal permeability dysregulation in the context of amputation may lead to pathology in both regenerative and non-regenerative organisms. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/610385v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@81b022org.highwire.dtl.DTLVardef@52c2e9org.highwire.dtl.DTLVardef@17a5f93org.highwire.dtl.DTLVardef@118b8f6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Defining how oncogenic and developmental mutations of PIK3R1 alter the regulation of class IA phosphoinositide 3-kinases

The class IA PI3Ks are key signalling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders. Mutations in the p85 regulatory subunit encoded by PIK3R1 can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations activate both the p110/p110{delta} catalytic subunits. We find that the oncogenic Q572* truncation of PIK3R1 disrupts all inhibitory inputs, with p110 being hyper-activated compared to p110{delta}. In addition, we find that the R649W mutation in the cSH2 of PIK3R1 decreases sensitivity to activation by receptor tyrosine kinases. This work reveals novel insight into isoform specific regulation of p110s by p85.\n\nHighlights- An oncogenic variant of p85, Q572*, leads to hyper-activation of p110 compared to p110{delta}\n- HDX-MS revealed that Q572* leads to disruption of all inhibitory interfaces in p110\n- A SHORT syndrome mutation in p85 leads to decreased sensitivity to RTKs for p110/{delta}

biochemistry↗