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Abstract Background Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance. Results Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease. Conclusions Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.

Ligand-gated ion channels are an ionotropic receptor subtype characterized by the binding of an extracellular ligand, followed by the transient passage of ions through a transmembrane pore. Ligand-gated ion channels are commonly subcategorized into three superfamilies: purinoreceptors, glutamate receptors, and Cys-loop receptors. This classification is based on the differing topographical morphology of the receptors, which in turn confers functional differences. Ligand-gated ion channels have a diverse spatial and temporal expression which implicate them in key cellular processes. Given that the transcellular electrochemical gradient is finely tuned in eukaryotic cells, any disruption in this homeostasis can contribute to aberrancies, including altering the activity of pro-tumorigenic molecular pathways, such as the MAPK/ERK, RAS, and mTOR pathways. Ligand-gated ion channels therefore serve as a potential targetable system for cancer therapeutics. In this review, we analyze the role that each of the three ligand-gated ion channel superfamilies has concerning tumor proliferation and as a target for the treatment of cancer symptomatology. [ABSTRACT FROM AUTHOR]

Ligand-gated ion channels are an ionotropic receptor subtype characterized by the binding of an extracellular ligand, followed by the transient passage of ions through a transmembrane pore. Ligand-gated ion channels are commonly subcategorized into three superfamilies: purinoreceptors, glutamate receptors, and Cys-loop receptors. This classification is based on the differing topographical morphology of the receptors, which in turn confers functional differences. Ligand-gated ion channels have a diverse spatial and temporal expression which implicate them in key cellular processes. Given that the transcellular electrochemical gradient is finely tuned in eukaryotic cells, any disruption in this homeostasis can contribute to aberrancies, including altering the activity of pro-tumorigenic molecular pathways, such as the MAPK/ERK, RAS, and mTOR pathways. Ligand-gated ion channels therefore serve as a potential targetable system for cancer therapeutics. In this review, we analyze the role that each of the three ligand-gated ion channel superfamilies has concerning tumor proliferation and as a target for the treatment of cancer symptomatology.

Background: Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates., Results: 21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV . In CPTAC, collagen IV protein was more abundant in advanced stages of disease., Conclusions: On spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC., Competing Interests: Competing interests: The corresponding author certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (ie. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: ACS, MTH, TCP, OEO, NHC, AEB, PAS, JN, CMS, NLF, PMRE, KYT, JAB, YCP, JD, LAM, WEG, and BLF have no relevant disclosures; BJM is an NCCN Kidney Cancer Panel Member and an advisor for Merck; RL received research support from Predicine, Veracyte, CG Oncology, Valar Labs, and Merck, is on the clinical trials committee for CG Oncology, is scientific advisor for Bristol Myers Squibb, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, and Janssen, and has received honoraria from SAI MedPartners, Solstice Health Communications, Putnam Associates, and UroToday; JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics; NS, SK, and MG are or formerly were employees of Nanostring.

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogelbased nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we showa broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical application.s [ABSTRACT FROM AUTHOR]

Diffusion-based communication is one of the most dominating forms in the micrometer and nanoscale communications. Generally, information is coded in molecules that are released by a transmitter nanomachine, propagated via a diffusion-based channel, and then received by a receiving nanomachine (called receiver). The receiver considered in this paper is equipped with multiple ligand receptors. The molecular communication system in this paper is single hop and SISO. Namely, there is only a channel connecting a pair of transmitter and receiver. While most literature considers either the channel or the receptors, this paper proposes a channel model that takes into account both the diffusion-based channel and the ligand-based receiver. The channel capacity under such model is analyzed, which studies the impact of different parameters at both channel and the receiver on the performance of the molecular communication system. We establish a digital channel model based on the on-off keying and time slot scheme. A capacity expression is derived with consideration of the effects of the channel memory and ligand-receptor binding mechanisms. The numerical results show that the overall channel capacity is restricted by the physical parameters of diffusion channel and ligand receptors. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Substrate-binding proteins (SBP) are associated with a wide variety of protein complexes. The proteins are part of ATP-binding cassette transporters for substrate uptake, ion gradient driven transporters, DNA-binding proteins, as well as channels and receptors from both pro- and eukaryotes. A wealth of structural and functional data is available on SBPs, with over 120 unique entries in the Protein Data Bank (PDB). Over a decade ago these proteins were divided into three structural classes, but based on the currently available wealth of structural data, we propose a new classification into six clusters, based on features of their three-dimensional structure. [Copyright &y& Elsevier]

Biomarker expression both on the cell surface and in serum is directly related to the pathological process of tumor. Based on the interaction between the ligand and the protein receptor, a label-free photoelectrochemical (PEC) biosensing interface with good antifouling ability was proposed for tumor cell detection. TiO 2 nanotube (NT) arrays were used as the substrate to enhance the ability of the biosensor to capture the target. Mercapto-terminated 8-arm poly(ethylene glycol) was introduced onto the electrode surface by the deposition of Au nanoparticles on TiO 2 NTs, creating an antifouling molecular layer. The recognition ligand hyaluronic acid (HA) was functionalized by dopamine and introduced onto the sensing surface based on the unique chelating interaction between the catechol group and the titanium atom. Benefitting from the specific recognition of HA with CD44 and the 3D porous structures of NTs, the constructed PEC biosensor showed excellent abilities toward the detection of MDA-MB-231 breast tumor cells and the soluble form of CD44. The ligand-receptor PEC sensing strategy has promising potential for the detection of tumor cells and protein biomarkers.