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Cao, J.

Publications and source records attributed to Cao, J..

At least 91 records · Page 5Linked to original sources
bioRxiv2024

Deep generative models generate mRNA sequences with enhanced translation capacity and stability

Despite the tremendous success of messenger RNA (mRNA) COVID-19 vaccines, the extension of this modality to a broader spectrum of diseases necessitates substantial enhancements, particularly in the design of mRNAs with elevated expression levels and extended durability. Here we present GEMORNA, a deep generative model designed to generate novel mRNA coding sequences (CDSs) and untranslated regions (UTRs) with superior translation capacity, comparable to the sophisticated task of language translation and free-form poetry composition with accurate grammar and semantics. Our AI model was trained on an extensive collection of RNA sequences from diverse families, further enhanced with labeled data to refine its performance. Remarkably, we demonstrate that our AI-generated mRNAs exhibited 8.2-fold and 15.9-fold increases in firefly luciferase expression compared to benchmark mRNAs in two different cell types. Additionally, Our AI- designed COVID-19 mRNA vaccine elicited a 4-fold increase in anti-COVID antibody titer in mice relative to BNT162b2. Furthermore, GEMORNAs versatility extends to circular mRNA design, which we facilitated a 27-fold increase in human erythropoietin protein expression in vivo than a systematically optimized benchmark sequence. We also created circular mRNAs with substantial improvements in expression levels, durability and anti-tumor cell cytotoxicity in mRNA-transduced CAR-T cells compared with an experimentally validated benchmark. In summary, GEMORNA generates novel mRNA sequences with significant performance improvements and has the potential to enable a wide range of therapeutic and vaccine applications.

synthetic biology↗
bioRxiv2024

TRIM32 inhibits Venezuelan Equine Encephalitis Virus Infection by targeting a late step in viral entry

Alphaviruses are mosquito borne RNA viruses that are a reemerging public health threat. Alphaviruses have a broad host range, and can cause diverse disease outcomes like arthritis, and encephalitis. The host ubiquitin proteasome system (UPS) plays critical roles in regulating cellular processes to control the infections with various viruses, including alphaviruses. Previous studies suggest alphaviruses hijack UPS for virus infection, but the molecular mechanisms remain poorly characterized. In addition, whether certain E3 ubiquitin ligases or deubiquitinases act as alphavirus restriction factors remains poorly understood. Here, we employed a cDNA expression screen to identify E3 ubiquitin ligase TRIM32 as a novel intrinsic restriction factor against alphavirus infection, including VEEV-TC83, SINV, and ONNV. Ectopic expression of TRIM32 reduces alphavirus infection, whereas depletion of TRIM32 with CRISPR-Cas9 increases infection. We demonstrate that TRIM32 inhibits alphaviruses through a mechanism that is independent of the TRIM32-STING-IFN axis. Combining reverse genetics and biochemical assays, we found that TRIM32 interferes with genome translation after membrane fusion, prior to replication of the incoming viral genome. Furthermore, our data indicate that the monoubiquitination of TRIM32 is important for its antiviral activity. Notably, we also show two TRIM32 pathogenic mutants R394H and D487N, related to Limb-girdle muscular dystrophy (LGMD), have a loss of antiviral activity against VEEV-TC83. Collectively, these results reveal that TRIM32 acts as a novel intrinsic restriction factor suppressing alphavirus infection and provides insights into the interaction between alphaviruses and the host UPS. Author summaryDue to climate change, wildlife habitat loss, and human activities, alphavirus infections are a growing threat to public health. The host UPS has critical role in virus-host interaction, but how the UPS impact alphavirus infection is not completely understood. In this study, we found that the E3 ubiquitin ligase TRIM32 inhibits diverse alphaviruses in multiple cell types. Mechanistically, TRIM32 impairs primary translation of incoming viral genome in a manner that depends on. monoubiquitination of TRIM32. Additionally, disease-associated alleles of TRIM32 have a loss-of-function with respect to viral inhibition. Together, these findings uncover a novel biological function of TRIM32 in regulating alphavirus infection and provide important insights into the interplay between alphaviruses and the host USP.

microbiology↗
bioRxiv2024

Multi-omics Reveals Immune Response and Metabolic Profiles during High-Altitude Mountaineering

The physiological perturbations induced by high-altitude exposure in mountain climbers, manifesting as metabolic and immunologic deviations, have been previously reported but are not fully understood. In this study, we obtained longitudinal multi-omic profiles of blood samples for healthy mountain climbers during two mountaineering stages (acclimatization and extreme altitude mountaineering). Our integrative assay included metabolomics and lipidomics profiling of plasma coupled with single-cell transcriptomic analysis of 375,722 immune cells. Longitudinal analysis revealed dynamic immune response profiles, during the acclimatization period, characterized by the downregulation of inflammatory responses in monocytes and classical dendritic cells (cDCs) and an increase in the proportion of cytotoxic CD8+ T cells with enhanced immune effector processes. In contrast, during extreme altitude mountaineering, the activation of inflammatory responses and impairment of T cell effector function were observed, concomitant with an increased cellular response to hypoxia and oxidative stress pathways. Furthermore, we found upregulated glycolysis and antioxidant gene expression during extreme altitude mountaineering, which was primarily orchestrated by HIF1A and NFE2L2, while decreased expression of these genes was observed in dysregulated plasmacytoid dendritic cells (pDCs). Finally, high-resolution plasma metabolic analysis revealed significant alterations in the metabolism of climbers, involving enhanced glutamine and fatty acid metabolism.

bioinformatics↗
bioRxiv2024

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation

Background and ObjectiveProstate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. MethodsA novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Resultsunveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. ConclusionThe lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

cancer biology↗
bioRxiv2024

Changes in growth, lanthanide binding, and gene expression in Pseudomonas alloputida KT2440 in response to light and heavy lanthanides

Pseudomonas alloputida KT2440 is a ubiquitous, soil-dwelling bacterium that metabolizes recalcitrant and volatile carbon sources. The latter are utilized by two redundant, Ca- and lanthanide (Ln)-dependent, pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ ADH), PedE and PedH, whose expression is regulated by Ln availability. P. alloputida KT2440 is the best-studied, non-methylotroph in the context of Ln-utilization. We report the most comprehensive differential gene expression analysis, to date, for any Ln-utilizing microbe. Combined with microfluidic cultivation and single-cell elemental analysis, we studied the impact of light and heavy Ln when growing P. alloputida KT2440 with 2-phenylethanol as the carbon and energy source. Light Ln (La, Ce, Nd) and a mixture of light and heavy Ln (La, Ce, Nd, Dy, Ho, Er, Yb) had a positive effect on growth, while supplementation with heavy Ln (Dy, Ho, Er, Yb) exerted fitness costs. These were likely a consequence of mismetallation and oxidative stress. Gene expression analysis showed that the Ln sensing and signaling machinery, the two-component system PedS2R2 and PedH, responds differently to (non-)utilizable Ln. We broadened the understanding of the Ln switch in P. alloputida KT2440 and could show that it operates as a dimmer switch, modulating the pool of PQQ ADH dependent on Ln availability. Determined quantities of cell-associated Ln suggest a role for Ln beyond alcohol oxidation. The usability of Ln governs the response of P. alloputida KT2440 to different Ln elements. ImportanceThe Ln switch, the inverse regulation of Ca- and Ln-dependent PQQ ADH dependent on Ln availability in organisms featuring both, is central to our understanding of Ln utilization. Although the preference of bacteria for light Ln is well known, the effect of different Ln, light and heavy, on growth and gene expression has rarely been studied. We provide evidence for a dimmer switch-like regulation of Ca- and Ln-dependent PQQ ADH in P. alloputida KT2440, and could show that the response to (non-)utilizable Ln differs depending on the element. Ln commonly co-occur in nature. Our findings underline that Ln-utilizing microbes must be able to discriminate between Ln to use them effectively. Considering the prevalence of Ln-dependent proteins in many microbial taxa, more work addressing Ln sensing and signaling is needed. Ln availability likely necessitates different adaptations regarding Ln utilization.

microbiology↗
bioRxiv2024

pH-Sensitive Nanodroplets for Controlled Delivery of Berberine Chloride

BackgroundThe development of nanocarriers with precise control over drug release is crucial for targeted therapy. This study focuses on the design and optimization of pH-sensitive gelatin/perfluorohexane (PFH) nanodroplets loaded with berberine chloride, a model drug relevant to traditional Chinese medicine. Subjects and MethodsNanodroplets were prepared using an emulsion technique, with optimization of parameters including homogenization rate, polymer concentration, surfactant, drug, and perfluorocarbon conte nt. ResultsThe optimized formulation resulted in nanodroplets with a mean particle size of 281.7 nm and a drug encapsulation efficiency of 66.8 {+/-} 1.7%. Characterization studies confirmed successful encapsulation and pH-responsive behavior. Ultrasound stimulation significantly enhanced drug release, with 150 kHz frequency proving more effective than 1 MHz. Stability studies demonstrated prolonged stability over one month at 4{degrees}C. Following 10 minutes of ultrasound irradiation, the nanodroplets exhibited 89.4% cumulative drug release. ConclusionsIn conclusion, these pH-sensitive nanodroplets show potential for delivering berberine chloride in a controlled manner, connecting traditional Chinese medicine with contemporary drug delivery methods.

biophysics↗
bioRxiv2024

Steppe Ancestry in western Eurasia and the spread of the Germanic Languages

Today, Germanic languages, including German, English, Frisian, Dutch and the Nordic languages, are widely spoken in northwest Europe. However, key aspects of the assumed arrival and diversification of this linguistic group remain contentious1-3. By adding 712 new ancient human genomes we find an archaeologically elusive population entering Sweden from the Baltic region by around 4000 BP. This population became widespread throughout Scandinavia by 3500 BP, matching the contemporaneous distribution of Palaeo-Germanic, the Bronze Age predecessor of Proto-Germanic4-6. These Baltic immigrants thus offer a new potential vector for the first Germanic speakers to arrive in Scandinavia, some 800 years later than traditionally assumed7-12. Following the disintegration of Proto-Germanic13-16, we find by 1650 BP a southward push from Southern Scandinavia into presumed Celtic-speaking areas, including Germany, Poland and the Netherlands. During the Migration Period (1575-1375 BP), we see this ancestry representing West Germanic Anglo-Saxons in Britain, and Langobards in southern Europe. We find a related large-scale northward migration into Denmark and South Sweden corresponding with historically attested Danes and the expansion of Old Norse. These movements have direct implications for multiple linguistic hypotheses. Our findings show the power of combining genomics with historical linguistics and archaeology in creating a unified, integrated model for the emergence, spread and diversification of a linguistic group.

genetics↗
bioRxiv2024

A Panoramic View of Cell Population Dynamics in Mammalian Aging

To elucidate the aging-associated cellular population dynamics throughout the body, here we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes. This comprehensive dataset allowed us to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Our panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Moreover, we investigated aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte-dependent. The breadth and depth of our cell-omics methodology not only enhance our comprehension of cellular aging but also lay the groundwork for exploring the complex regulatory networks among varied cell types in the context of aging and aging-associated diseases. One Sentence SummaryPanSci, a single-cell transcriptome atlas of over 20 million cells throughout the mouse lifespan, unveils the temporal architecture of aging-associated cellular population dynamics, organ-specific immune cell shifts, and the lymphocytes role in organismal aging.

genomics↗
bioRxiv2024

Unveiling Tryptophan Dynamics and Functions Across Model Organisms via Quantitative Imaging

Tryptophan is an essential amino acid involved in many cellular processes in vertebrates. Systemic and quantitative measurement of tryptophan is crucial for evaluating its essential role as a precursor of serotonin and kynurenine, key neuromodulators affecting neural and immune functions. We utilized a robust and highly responsive ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, and human serum. At the cellular scale, these analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated tryptophan metabolites serotonin and kynurenine levels, which is associated with the prolonged sleep duration. The reduction of zebrafish plasma tryptophan was mirrored in patients with inflammation symptoms and could serve as a biochemical marker of inflammation. In summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and functions across scales and species and suggests that tryptophan metabolic processes link the immune response and animal behavior.

biochemistry↗
bioRxiv2024

Harnessing the regenerative potential of interleukin11 to enhance heart repair

Balancing between regenerative processes and fibrosis is crucial for heart repair, yet strategies regulating this balance remain a barrier to developing therapies. While Interleukin11 (IL11) is known as a fibrotic factor, its contribution to heart regeneration is poorly understood. We uncovered that il11a, an Il11 homolog in zebrafish, can trigger robust regenerative programs in zebrafish hearts, including cardiomyocytes proliferation and coronary expansion, even in the absence of injury. However, prolonged il11a induction in uninjured hearts causes persistent fibroblast emergence, resulting in fibrosis. While deciphering the regenerative and fibrotic effects of il11a, we found that il11-dependent fibrosis, but not regeneration, is mediated through ERK activity, suggesting to potentially uncouple il11a dual effects on regeneration and fibrosis. To harness the il11as regenerative ability, we devised a combinatorial treatment through il11a induction with ERK inhibition. This approach enhances cardiomyocyte proliferation with mitigated fibrosis, achieving a balance between regenerative processes and fibrosis. Thus, we unveil the mechanistic insights into regenerative il11 roles, offering therapeutic avenues to foster cardiac repair without exacerbating fibrosis.

developmental biology↗
bioRxiv2023

Quantitative cell morphology in C. elegans embryos reveals regulations of cell volume asymmetry

The dynamics of cellular morphology throughout development are crucial for morphogenesis and organogenesis, yet their systematic characterization remains a significant challenge. By integrating both nuclear position and advanced cell membrane labeling, we develop a novel method that enables the segmentation of surfaces for over 95% of cells produced during Caenorhabditis elegans embryogenesis. With this method, we segment eight wild-type and four perturbed embryos. The output, including cell identity, shape, volume, surface and contact area, can be visualized using our custom software. We demonstrate that signaling interactions, such as Notch and Wnt, regulate not only the asymmetry of cell fate but also the asymmetry of cell volume in conjunction with mechanical compression. Furthermore, we find that the asymmetries of fate and volume are generally interconnected. ONE SENTENCE SUMMARYSystematic quantification of cell morphology with resolved cell lineage and cell fate in developing C. elegans embryo uncovers multimodal regulations of cell size. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/567849v1_ufig1.gif" ALT="Figure 1"> View larger version (114K): org.highwire.dtl.DTLVardef@1b7d0fforg.highwire.dtl.DTLVardef@fa28b1org.highwire.dtl.DTLVardef@185a0deorg.highwire.dtl.DTLVardef@478a2_HPS_FORMAT_FIGEXP M_FIG C_FIG Potential Cover/Featured Image: Smiling "ghost" face of C. elegans embryo. Center: shown are skins (colored in red, dorsal view with anterior to the bottom) of a 400-celled C. elegans embryo. Cells not covered by the skins are colored in gray, green, blue, and transparent yellow, respectively. Internal and external circles: confocal fluorescence images (GFP for cell nucleus and mCherry for cell membrane) and reconstructed cell morphologies of the C. elegans embryo from the 2- to 550-cell stages respectively, connected with images of a C. elegans adult expressing the same markers.

developmental biology↗
bioRxiv2023

Pervasive aggregation and depletion of host and viral proteins in response to cysteine-reactive electrophilic compounds

Protein homeostasis is tightly regulated, with damaged or misfolded proteins quickly eliminated by the proteasome and autophagosome pathways. By co-opting these processes, targeted protein degradation technologies enable pharmacological manipulation of protein abundance. Recently, cysteine-reactive molecules have been added to the degrader toolbox, which offer the benefit of unlocking the therapeutic potential of undruggable protein targets. The proteome-wide impact of these molecules remains to be fully understood and given the general reactivity of many classes of cysteine-reactive electrophiles, on- and off-target effects are likely. Using chemical proteomics, we identified a cysteine-reactive small molecule degrader of the SARS-CoV-2 non- structural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host chaperones together with activation of global cell stress response pathways. We find that cysteine-reactive electrophiles increase global protein ubiquitylation, trigger proteasome activation, and result in widespread aggregation and depletion of host proteins, including components of the nuclear pore complex. Formation of stress granules was also found to be a remarkably ubiquitous cellular response to nearly all cysteine-reactive compounds and degraders. Collectively, our study sheds light on complexities of covalent target protein degradation and highlights untapped opportunities in manipulating and characterizing proteostasis processes via deciphering the cysteine-centric regulation of stress response pathways.

biochemistry↗
bioRxiv2023

Innate immune memory after brain injury drives inflammatory cardiac dysfunction

The enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects of brain injury on systemic immunity have so far been barely investigated. Here, we identified myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Using single-cell sequencing, we identified persistent pro-inflammatory transcriptomic changes in resident monocytes/macrophages in multiple organs one month after experimental ischemic brain injury, which was particularly abundant in the heart and associated with the development of cardiac fibrosis and diastolic dysfunction. A similar phenotype was seen in myocardial autopsy samples from stroke versus control patients. We observed chronic functional changes in myeloid hematopoiesis driven by post-stroke IL-1{beta}-mediated epigenetic changes. These alterations could be transplanted to naive recipient mice and were sufficient to induce cardiac dysfunction. By effectively blocking the trafficking of pro-inflammatory monocytes from the bone marrow to the heart using a dual CCR2/5 inhibitor, we successfully prevented post-stroke cardiac dysfunction. This approach holds promising potential as a novel immune-targeted secondary prevention therapy. We anticipate that the epigenetic immune reprogramming mechanisms detailed here for the brain-heart axis could be generalized to provide a novel framework for explaining the development of various comorbidities after acute tissue injury in remote organs.

immunology↗
bioRxiv2023

CD8 T-cell dysfunction is linked with CAR T-cell failure and can be mitigated by a non-alpha IL-2 agonist, pegenzileukin

Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CAR T-cell activity can lead to therapeutic failure and dismal outcome. Using single cell RNA-sequencing of rrLBCL tumors, we identify a prominent population of clonally expanded dysfunctional CAR+ CD8 T-cells indicative of ongoing tumor cell engagement, proliferation, and dysfunction at the time of progression from CAR T-cell therapy. Furthermore, we show that rrLBCL patient-derived CAR T-cells are more prone to dysfunction and loss of cytotoxicity compared to healthy donor-derived CAR T-cells. Using both antigen-driven and CAR-driven models of T-cell dysfunction, we show that pegenzileukin, a non-alpha IL2 agonist, can prevent T-cell dysfunction. In both in vitro and in vivo CAR T-cell models, pegenzileukin improved T-cell expansion and tumor control. This provides pre-clinical rational for use of pegenzileukin in combatting T-cell dysfunction, a central mechanism of CAR T-cell failure. HIGHLIGHTSO_LITumor-infiltrating CD8 CAR T-cells show clonal expansion and dysfunction at the time of progression. C_LIO_LIrrLBCL patient-derived CAR T-cells are more prone to dysfunction compared to healthy-donor-derived CAR T-cells. C_LIO_LIPegenzileukin, a non-alpha IL2 agonist, rescues antigen- and CAR-driven CD8 T-cell dysfunction and improves CAR T-cell responses in vivo. C_LI

immunology↗
bioRxiv2023

Defense mechanism of a bacterial retron supramolecular assembly

Retrons are a class of multigene antiphage defense system typically consisting of a retron reverse transcriptase, a non-coding RNA, and a cognate effector. Although the triggers for several retron systems have been discovered recently, the full picture of how retron systems sense invading phages and mediate defense remains to be elucidated. Here, we focus on the retron Ec86 defense system and report its modes of activation and action. We identified a phage-encoded DNA cytosine methyltransferase (Dcm) as the trigger of the Ec86 system and show that Ec86 senses msDNA methylation and becomes activated. We further determined the structure of a tripartite retron Ec86 supramolecular assembly, which is primed for activation by Dcm, and demonstrated that the activated system confers defense through depletion of nucleoside derivatives. These findings emphasize the role of retrons being a second line of defense and highlight an emerging theme of anti-phage defense through supramolecular complex assemblies.

microbiology↗
bioRxiv2023

Dendrimeric DNA Coordinate Barcoding Design for Spatial RNA Sequencing

Spatially resolved transcriptomic technologies show promise in revealing complex pathophysiological processes, but developing sensitive, high-resolution, and cost-effective methodology is challenging. Here, we report a dendrimeric DNA coordinate barcoding design for spatial RNA sequencing (Decoder-seq). This technology combined dendrimeric nano-substrates with microfluidic coordinate barcoding to generate high-density spatial DNA arrays with deterministically combinatorial barcodes in a resolution-flexible and cost-effective manner ([~]$0.5/mm2). Decoder-seq achieved high RNA capture efficiency, [~]68.9% that of in situ sequencing, and enhanced the detection of lowly expressed genes by [~]five-fold compared to 10x Visium. Decoder-seq visualized a spatial single-cell atlas of mouse hippocampus at near-cellular resolution (15 m) and revealed dendrite-enriched mRNAs. Application to renal cancers dissected the heterogeneous tumor microenvironment of two subtypes, and identified spatial gradient expressed genes with the potential in predicting tumor prognosis and progression. Decoder-seq is compatible with sensitivity, resolution, and cost, making spatial transcriptomic analysis accessible to wider biomedical applications and researchers.

genomics↗
bioRxiv2023

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

cancer biology↗