The IL-4-IL-4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell.

IL-4 and IL-13 have non-redundant effects in olfaction, with loss of smell in mice evoked only by intranasal administration of IL-4, but not IL-13. IL-4-evoked pathophysiological effects on olfaction is independent of compromised structural integrity of the olfactory neuroepithelium. IL-4-IL-4Rα signaling modulates neuronal crosstalk with immune cells, suggesting a functional link between olfactory impairment and neuroinflammation.

GENIX enables comparative network analysis of single-cell RNA sequencing to reveal signatures of therapeutic interventions.

Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cellular responses to perturbations such as therapeutic interventions and vaccines. Gene relevance to such perturbations is often assessed through differential expression analysis (DEA), which offers a one-dimensional view of the transcriptomic landscape. This method potentially overlooks genes with modest expression changes but profound downstream effects and is susceptible to false positives.

Pure estrogen receptor antagonists potentiate capecitabine activity in ESR1-mutant breast cancer.

The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment.

Scaling up single-cell RNA-seq data analysis with CellBridge workflow.

Summary: Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of gene expression at the individual cell level, unraveling unprecedented insights into cellular heterogeneity. However, the analysis of scRNA-seq data remains a challenging and time-consuming task, often demanding advanced computational expertise, rendering it impractical for high-volume environments and applications. We present CellBridge, an automated workflow designed to simplify the standard procedures entailed in scRNA-seq data analysis, eliminating the need for specialized computational expertise.

A marker gene-based method for identifying the cell-type of origin from single-cell RNA sequencing data.

Single-cell RNA sequencing (scRNA-seq) experiments provide opportunities to peer into complex tissues at single-cell resolution. However, insightful biological interpretation of scRNA-seq data relies upon precise identification of cell types. The ability to identify the origin of a cell quickly and accurately will greatly improve downstream analyses.

Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma.

Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response.

Visinity: Visual Spatial Neighborhood Analysis for Multiplexed Tissue Imaging Data.

New highly-multiplexed imaging technologies have enabled the study of tissues in unprecedented detail. These methods are increasingly being applied to understand how cancer cells and immune response change during tumor development, progression, and metastasis, as well as following treatment. Yet, existing analysis approaches focus on investigating small tissue samples on a per-cell basis, not taking into account the spatial proximity of cells, which indicates cell-cell interaction and specific biological processes in the larger cancer microenvironment.

Temporal and spatial topography of cell proliferation in cancer.

Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation metrics. Across diverse cancers, proliferative architecture is organized at two spatial scales: large domains, and smaller niches enriched for specific immune lineages.

Scope2Screen: Focus+Context Techniques for Pathology Tumor Assessment in Multivariate Image Data.

Inspection of tissues using a light microscope is the primary method of diagnosing many diseases, notably cancer. Highly multiplexed tissue imaging builds on this foundation, enabling the collection of up to 60 channels of molecular information plus cell and tissue morphology using antibody staining. This provides unique insight into disease biology and promises to help with the design of patient-specific therapies.

Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients.

Multimodal platform for assessing drug distribution and response in clinical trials.

Background: Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy.

Methods: Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tissue drug distribution was measured with MALDI-MSI.

HSF1 phase transition mediates stress adaptation and cell fate decisions.

Under proteotoxic stress, some cells survive whereas others die. The mechanisms governing this heterogeneity in cell fate remain unknown. Here we report that condensation and phase transition of heat-shock factor 1 (HSF1), a transcriptional regulator of chaperones, is integral to cell-fate decisions underlying survival or death.

Highly multiplexed immunofluorescence images and single-cell data of immune markers in tonsil and lung cancer.

In this data descriptor, we document a dataset of multiplexed immunofluorescence images and derived single-cell measurements of immune lineage and other markers in formaldehyde-fixed and paraffin-embedded (FFPE) human tonsil and lung cancer tissue. We used tissue cyclic immunofluorescence (t-CyCIF) to generate fluorescence images which we artifact corrected using the BaSiC tool, stitched and registered using the ASHLAR algorithm, and segmented using ilastik software and MATLAB. We extracted single-cell features from these images using HistoCAT software.

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation.

Purpose: Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options. We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition and in syngeneic mouse models using genetic and pharmacologic tools.

The first Autumn School on Proteostasis: from molecular mechanisms to organismal consequences.

The first Autumn School on Proteostasis was held at the Mediterranean Institute for Life Sciences (MedILS) in Split, Croatia, from November 12th-16th, 2018, bringing together 44 graduate students and postdoctoral fellows and 22 principal investigators from around the world. This meeting was geared towards providing students with an in-depth understanding of the field of proteostasis, with the aim of broadening their perspectives of the field. Session topics covered multiple aspects of cellular and organismal proteostasis, including fundamental principles, responses to heat shock, aging and disease, and protein folding, misfolding, and degradation.

Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity.

Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity.

Constant rate of p53 tetramerization in response to DNA damage controls the p53 response.

The dynamics of the tumor suppressor protein p53 have been previously investigated in single cells using fluorescently tagged p53. Such approach reports on the total abundance of p53 but does not provide a measure for functional p53. We used fluorescent protein-fragment complementation assay (PCA) to quantify in single cells the dynamics of p53 tetramers, the functional units of p53.

Activation and control of p53 tetramerization in individual living cells.

Homo-oligomerization is found in many biological systems and has been extensively studied in vitro. However, our ability to quantify and understand oligomerization processes in cells is still limited. We used fluorescence correlation spectroscopy and mathematical modeling to measure the dynamics of the tetramers formed by the tumor suppressor protein p53 in single living cells.

Basal dynamics of p53 reveal transcriptionally attenuated pulses in cycling cells.

The tumor suppressor p53 is activated by stress and leads to cellular outcomes such as apoptosis and cell-cycle arrest. Its activation must be highly sensitive to ensure that cells react appropriately to damage. However, proliferating cells often encounter transient damage during normal growth, where cell-cycle arrest or apoptosis may be unfavorable.

The mechanism of sudden stripe formation during dorso-ventral patterning in Drosophila.

The front and back (ventral and dorsal part respectively) of arthropods and chordates are defined by a highly conserved mechanism during early embryonic development [De Robertis and Kuroda in Annu. Rev. Cell Dev.