Biology subjects

Cheng, F.

Publications and source records attributed to Cheng, F..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Single-cell digital twins identify drug targets and repurposable medicine in Alzheimers disease

Alzheimers disease (AD) is a complex and poorly understood neurodegenerative disorder without sufficiently effective treatments. Novel approaches to identify FDA-approved drugs that may hold potential for mitigating symptoms of AD hold promise for addressing this problem. One such strategy is the use of digital twins (DTs), which are virtual representations of physical entities that facilitate therapeutic target identification by accurately characterizing disease heterogeneities in real time through continuous feedback and dynamic model updates. In this study, we developed a single-cell digital twin (scDT) framework using single-nuclei RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) data from the middle temporal gyrus of 84 donors across 4 degrees of AD neuropathological change (ADNC). We observed differential gene expression for six major cell types intensified at severe ADNC. We also constructed cell type-specific transcription factor (TF)-target gene networks by leveraging peak-to-gene linkages and motif enrichment analyses. By integrating genome-wide association study (GWAS) loci with cell type-specific cis-regulatory DNA elements (CREs), we identified 141 ADNC-associated genes. Using gene set enrichment analysis (GSEA) and network proximity analysis, we identified 13 candidate repurposable drugs that were associated with these ADNC-associated genes. In summary, we constructed a single-cell digital twin (scDT) framework cell type-specific target identification and drug repurposing in AD and other complex diseases if broadly applied.

bioinformatics↗

bioRxiv2024

CRISPR-Cas supervises diverse anti-phage defense systems

A variety of bacterial anti-phage systems have recently been discovered1-3, but how these systems synergize to defend against diverse phages remains poorly understood. Here, we report that the adaptive immune system CRISPR-Cas supervises the expression of diverse immune systems by exploiting the regulatory CRISPR RNA-like RNAs (crlRNAs). The crlRNAs target and inhibit the promoters of various immune systems, including the newly characterized Nezha and Gabija, as well as eight previously unrecognized systems that feature distinct defensive domains. Notably, CRISPR regulation balances the expression level of these systems to ensure effective anti-phage activity while avoiding their autoimmunity risks. In return, the supervised immune systems trigger abortive infections when CRISPR-Cas is inhibited by viral anti-CRISPR proteins, thereby offering an anti-anti-CRISPR protection at the population level. Moreover, these systems complement CRISPR immunity with a differing anti-phage profile. These findings highlight the pivotal role of CRISPR-Cas in orchestrating a diverse range of immune systems and showcase the delicate synergy among the multilayered defense strategies in prokaryotes.

microbiology↗

bioRxiv2024

Deciphering the thiolactonization mechanism in thiolactomycin biosynthesis

Thiolactomycin (1), which features a unique{gamma} -thiolactone ring, is a promising antibiotic candidate that specifically targets bacterial type II fatty acid synthase. Despite extensive studies on its pharmacological activities, modes of action, and chemical synthesis, the enzymatic processes responsible for forming the activity-determining{gamma} -thiolactone ring have remained largely unknown. Here, we resolve this problem by revealing that the condensation and heterocyclization (Cy) domain of the nonribosomal peptide synthetase (NRPS) TlnC (TlnCCy), along with the cytochrome P450 enzyme TlnA, cooperatively enable the{gamma} -thiolactone assembly. TlnCCy mediates an unusual sulfurtransfer reaction to sulfurate the polyketide intermediate, generating a thiocarboxylate intermediate. Subsequently, TlnA acts as a{gamma} -thiolactone synthase, converting the linear thiocarboxylate intermediate into 1 via a distal radical-based cyclization mechanism. These findings not only expand the functional and catalytic repertoires of NRPS Cy domains and P450 enzymes, but also highlight a special enzymatic strategy for{gamma} -thiolactone biosynthesis in nature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/629141v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@7e0ad2org.highwire.dtl.DTLVardef@f86b80org.highwire.dtl.DTLVardef@159d136org.highwire.dtl.DTLVardef@1b633ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Phage CRISPR-like regulatory RNAs silence bacterial adaptive and innate immunity

CRISPR RNAs (crRNAs) encoded by CRISPR arrays direct Cas nucleases against viruses. Some CRISPR-Cas loci also contain mini-arrays encoding crRNA-like RNAs (crlRNAs), which modulate transcription of cas or associated toxin genes that safeguard CRISPR-Cas activity. Here, we report that phages hijack these host crlRNA regulatory circuits to suppress bacterial immunity. Viral crlRNAs compete with host crRNAs for Cas protein binding and reprogram Cas proteins to silence their own expression or suppress transcription of CRISPR-safeguarding toxins. These anti-defense crlRNAs are found across diverse phages and plasmids, frequently organized into multiplexed transcriptional units resembling CRISPR arrays, and often synergize with co-encoded anti-CRISPR proteins to disable hierarchical host immune responses. Furthermore, we demonstrate that these compact viral crlRNA architectures can be harnessed for efficient mammalian genome editing. Our findings uncover widespread viral hijacking of host Cas proteins via crlRNAs, highlighting the recurrent exaptation of CRISPR-Cas regulatory functions to counter multilayered bacterial immune defenses.

microbiology↗

bioRxiv2024

Identification of SLC35A1 as an essential host factor for the transduction of multi-serotype recombinant adeno-associated virus (AAV) vectors

We conducted a genome-wide CRISPR/Cas9 screen in suspension 293-F cells transduced with rAAV5. The highly selected genes revealed after two rounds of screens included the previously reported KIAA039L, TM9SF2, and RNF121, along with a cluster of genes involved in glycan biogenesis, Golgi apparatus localization and endoplasmic reticulum penetration. In this report, we focused on solute carrier family 35 member A1 (SLC35A1), a Golgi apparatus-localized cytidine 5-monophosphate-sialic acid (CMP-SIA) transporter. We confirmed that SLC35A1 knockout (KO) significantly decreased rAAV5 transduction to a level lower than that observed in KIAA0319L or TM9SF2 KO cells. Although SLC35A1 KO drastically reduced the expression of 2,6-linked SIA on the cell surface, the expression of 2,3-linked SIA, as well as the cell binding and internalization of rAAV5, were only moderately affected. Moreover, SLC35A1 KO significantly diminished the transduction of AAV multi-serotypes, including rAAV2 and rAAV3 which do not utilize SIAs for primary attachment. Notably, the SLC35A1 KO markedly increased transduction of rAAV9 and rAAV11, which primarily attach to cells via binding to galactose. Further analyses revealed that SLC35A1 KO significantly decreased vector nuclear import. More importantly, although the C-terminal cytoplasmic tail deletion ({Delta}C Tail) mutant of SLC35A1 did not drastically decrease SIA expression, it significantly decreased rAAV transduction, as well as vector nuclear import, suggesting the C-tail is critical in these processes. Furthermore, the T128A mutant significantly decreased SIA expression, but still supported rAAV transduction and nuclear import. These findings highlight the involvement of the CMP-SIA transporter in the intracellular trafficking of rAAV vectors post-internalization. IMPORTANCErAAV is an essential tool for gene delivery in the treatment of genetic disorders, yet the mechanisms of rAAV transduction remain partially understood. GPR108 is vital for the transduction of most rAAV vectors, but not for rAAV5. We aimed to identify host factors that impact AAV5 transduction akin to GPR108. Using a genome-wide CRISPR/Cas9 screen in 293-F cells, we identified SLC35A1, a Golgi apparatus-localized CMP-sialic acid transporter that transports CMP-sialic acid from cytoplasm into the Golgi apparatus for sialylation, is essential to rAAV transduction. Further studies across various AAV serotypes showed SLC35A1 significantly affects vector nuclear import post-internalization. These results underscore the crucial role of SLC35A1 in intracellular trafficking beyond the initial cell attachment of rAAV.

microbiology↗

bioRxiv2024

Proteolysis-targeting vaccines (PROTAVs) for robust tumor combination immunotherapy

Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8+ T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8+ T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large BrafV600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.

bioengineering↗

bioRxiv2024

A Molecular Image-based Explainable Artificial intelligence Framework Identifies Novel Candidate Antibiotics

The continued growth of antibiotic resistance and the slowing of antibiotic discovery poses a large challenge in fighting infectious diseases. Recent advances in Artificial intelligence (AI) technologies offer a time- and cost-effective solution for the rapid development of effective antibiotics. In this study, we presented an explainable AI framework from a pre-trained model using 10 million drug-like molecular images. Specifically, we created a fine-tuned ImageMol from experimental Staphylococcus aureus inhibition assays which contained 24,521 molecules consisting of 516 active compounds and 24,005 non-active compounds. Our optimized AI model achieved a strong AUROC of 0.926. The model was then used to predict the antibiotic activities from 10,247 FDA-approved, clinically investigational, or experimental molecules from the DrugBank database. After further filtering, 340 molecules were identified to have antibacterial behavior while simultaneously being dissimilar to known antibiotics. Finally, 76 candidates were identified as FDA-approved drugs for other applications. Thus, those candidates can be repurposed into needed novel antibiotics. We further illustrated explainable molecular images for top predicted candidate drugs via Gradient-weighted Class Activation Mapping (Grad-CAM) heatmap analysis. In summary, the presented molecular image-based AI model in drug discovery could be highly favorable due to its high performance, speed, and biological interpretation.

pharmacology and toxicology↗

bioRxiv2024

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter {gamma}-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

cancer biology↗

bioRxiv2024

Investigation of the mechanism of accelerated biodegradation of Paracoccus-KDSPL-02

Paracoccus-KDSPL-02 can accelerate to degrade penicillin G under light remain poorly understood, largely due to the lack of high-throughput genome engineering tools. Firstly, this study sequenced the genome of Paracoccus-KDSPL-02 and mined the genes that might be involved, and in order to understand in detail whether the expression of the mined genes changed during light. Further, for genes with altering transcriptional levels under light, this study obtained PROKKA_01468 which a photoreceptor protein in Paracoccus-KDSPL-02. In the end, for validating the function of PROKKA_01468, this study knocked down the sequence of the PROKKA_01468 by applying gene editing system, and the knockdown strain showed significant change in the rate of degradation of phenylacetic acid, which is the intermediate product of penicillin G degradation, by light compared with darkness, so that the PROKKA_01468 is the most effective photoreceptor protein in Paracoccus-KDSPL-02. SynopsisThis research elucidates a molecular mechanism capable of accelerating penicillin G degradation in wastewater, with significant implications for environmental science.

bioengineering↗

bioRxiv2024

Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

systems biology↗

bioRxiv2024

CAMKV Kinase Signaling Is a Novel Therapeutic Avenue with Prognostic Relevance in Neuroblastoma

Neuroblastoma (NB) can be a highly aggressive malignancy in children. However, the precise mechanisms driving NB tumorigenesis remain elusive. This study revealed the critical role of CREB phosphorylation in NB cell proliferation. By employing a CRISPR-Cas9 knockout screen targeting calcium/calmodulin-dependent protein kinase (CaMK) family members, we identified the CaM kinase-like vesicle-associated (CAMKV) protein as a kinase that mediates direct phosphorylation of CREB to promote NB cell proliferation. CAMKV was found to be a transcriptional target of MYCN/MYC in NB cells. CAMKV knockout and knockdown effectively suppressed NB cell proliferation and tumor growth both in vitro and in vivo. Bioinformatic analysis revealed that high CAMKV expression is significantly correlated with poor patient survival. High-risk NB frequently had high CAMKV protein levels by Immunohistochemical staining. Integrated transcriptomic and proteomic analyses of CAMKV knockdown cells unveiled downstream targets involved in CAMKV-regulated phosphorylation and signaling pathways, many of which are linked to neural development and cancer progression. We identified small molecule inhibitors targeting CAMKV and further demonstrated the efficacy of one inhibitor in suppressing NB tumor growth and prolonging the survival of mice bearing xenografted tumors. These findings reveal a critical role for CAMKV kinase signaling in NB growth and identified CAMKV kinase as a potential therapeutic target and prognostic marker for patients with NB.

cancer biology↗

bioRxiv2024

Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants

SCN2A gene disorders cover a wide range of medical conditions, from epileptic encephalopathies to neurodevelopmental disorders. The variants of these disorders, studied through electrophysiology, show complex behaviors that go beyond simple classification as either gain or loss of function. In our study, we simulated the biophysical effects of variants (R937C, V208E, S1336Y, and R853Q) to understand their impact. Our findings reveal that all these variants negatively affect the structural stability of the gene, with R937C being the most unstable. Specifically, R937C disrupts important charged interactions affecting sodium ion flow, while S1336Y introduces a new interaction that impacts the channels inactivation gate. Conversely, the variants V208E and R853Q, which are located in the voltage-sensing domains, have opposite effects: R853Q increases compactness and interaction, whereas V208E shows a decrease. Our computer-based method offers a scalable way to gain crucial insights into how genetic variants influence channel dysfunction and contribute to neurodevelopmental disorders. AUTHOR SUMMARYDespite numerous advancements in computational methods for predicting variant pathogenicity in the SCN2A gene, understanding the precise biophysical molecular mechanisms associated with each variant at the atomic level remains a challenge. Presently, variants are predominantly categorized as either gain or loss of function, often overlooking critical structural details associated with these variants. This study focuses on elucidating the molecular mechanisms linked to the four most common SCN2A variants using all-atom molecular dynamics simulations, employing three replicas for each system. Our findings offer insights into the potential mechanisms underlying these four variants, thereby providing explanations for the observed electrophysiological outcomes. This investigation significantly contributes to enhancing our comprehension of how SCN2A variants manifest in various diseases. It underscores the importance of unraveling the biophysical properties underlying potential disease mechanisms, which could potentially enhance diagnostic and therapeutic strategies for patients afflicted with SCN2A-related disorders.

biophysics↗

bioRxiv2024

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

The strongest risk factors for Alzheimers disease (AD) include the {chi}4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

neuroscience↗

bioRxiv2024

CRISPR-repressed toxin-antitoxin provides population-level immunity against diverse anti-CRISPR elements

Prokaryotic CRISPR-Cas systems are highly vulnerable to phage-encoded anti-CRISPR (Acr) factors. How CRISPR-Cas systems protect themselves remains unclear. Here, we uncovered a broad-spectrum anti-anti-CRISPR strategy involving a phage-derived toxic protein. Transcription of this toxin is normally reppressed by the CRISPR-Cas effector, but is activated to halt cell division when the effector is inhibited by any anti-CRISPR proteins or RNAs. We showed that this abortive infection-like effect efficiently expels Acr elements from bacterial population. Furthermore, we exploited this anti-anti-CRISPR mechanism to develop a screening method for specific Acr candidates for a CRISPR-Cas system, and successfully identified two distinct Acr proteins that enhance the binding of CRISPR effector to non-target DNA. Our data highlight the broad-spectrum role of CRISPR-repressed toxins in counteracting various types of Acr factors, which illuminates that the regulatory function of CRISPR-Cas confers host cells herd immunity against Acr-encoding genetic invaders, no matter they are CRISPR-targeted or not.

microbiology↗

bioRxiv2023

Insights into spinach domestication from genomes sequences of two wild spinach progenitors, Spinacia turkestanica and S. tetrandra

Cultivated spinach (Spinacia oleracea) is a dioecious species (with male and female flowers on separate individuals). We report high-quality genome assemblies for its two closest wild relatives, S. turkestanica and S. tetrandra, which are also dioecious, to study the genetics of spinach domestication. Using a combination of genomic approaches, we assembled genome sequences of both these species, and analysed them in comparison to the previously assembled S. oleracea genome. These species diverged approximately 6.3 million years ago (Mya), while cultivated spinach split from S. turkestanica (its probable direct progenitor) 0.8 Mya. A common feature of all three species is that all six chromosomes include very large gene-poor, repeat-rich regions. In S. oleracea, these correspond with pericentromeric regions with very low recombination rates in both male and female genetic maps, and we infer that the similar pericentromeric regions in the wild species also recombine rarely. Although these regions include a low proportion of Spinacia genes, many genes are nevertheless within them, and they must be considered when analyzing selection during domestication. As a first approach to the difficult question of detecting genes involved in spinach domestication, we characterized 282 structural variants (SVs) whose frequencies are higher in a set of spinach accessions than in the wild species, suggesting that they mark genome regions that have been selected during domestication. These regions include genes associated with leaf margin type and flowering time. We also describe evidence that the downy mildew resistance loci of cultivated spinach are derived from introgression from both wild spinach species.

genomics↗

bioRxiv2023

Two wild Spinacia species, S. turkestanica and S. tetrandra, genomes reveal a sex chromosome turnover in the genus

Spinach (Spinacia oleracea) is a dioecious species (with male and female flowers on separate individuals). Spinach and its closest wild relative, S. turkestanica, has homomorphic sex chromosomes, but the more distant relative S. tetrandra has heteromorphic sex chromosomes. We report high-quality genome assemblies for S. turkestanica and S. tetrandra. These diverged approximately 6.3 million years ago (Mya), while S. turkestanica split from S. oleracea much more recently, around 0.8 Mya, supporting previous suggestions that S. turkestanica is the direct progenitor of cultivated spinach. Using a combination of genomic approaches, we identified a sex-linked region (SLR) of [~]133 Mb in S. tetrandra. In all three species, the SLRs are within a large pericentromeric region of chromosome 4. We describe evidence that, in S. tetrandra, this region has completely stopped recombining in male meiosis, creating a large Y-linked region (YLR) that has partially degenerated; loss of recombination appears to have evolved in two events that created two "evolutionary strata", one of which and is highly rearranged, relative to the X. The SLRs of S. turkestanica and S. oleracea are much smaller: both include only a 10 Mb Y-specific region which is not detected in S. tetrandra. This was duplicated into a 14 Mb inverted region, and is termed the Y-duplicated region, or "YDR". These findings suggest that a turnover event created the YDR before these species diverged, replacing an extensive ancestral Y-linked region like the S. tetrandra YLR.

genomics↗

bioRxiv2023

Gene and allele specific expression underlying the electric signal divergence in African weakly electric fish

In the African weakly electric fish genus Campylomormyrus, electric organ discharge (EOD) signals are strikingly different in shape and duration among closely related species, contribute to pre-zygotic isolation and may have triggered an adaptive radiation. We performed mRNA sequencing on electric organs (EOs) and skeletal muscles (SMs; from which the EOs derive) from three species with short (0.4 ms), medium (5 ms), and long (40 ms) EODs and two different cross-species hybrids. We identified 1,444 up-regulated genes in EO shared by all five species/hybrids cohorts, rendering them candidate genes for EO-specific properties in Campylomormyrus. We further identified several candidate genes, including KCNJ2 and KLF5, their up-regulation may contribute to increased EOD duration. Hybrids between a short (C. compressirostris) and a long (C. rhynchophorus) discharging species exhibit EODs of intermediate duration and showed imbalanced expression of KCNJ2 alleles, pointing towards a cis-regulatory difference at this locus, relative to EOD duration. KLF5 is a transcription factor potentially balancing potassium channel gene expression, a crucial process for the formation of an EOD. Unraveling the genetic basis of the species-specific modulation of the EOD in Campylomormyrus is crucial for understanding the adaptive radiation of this emerging model taxon of ecological (perhaps even sympatric) speciation.

evolutionary biology↗

bioRxiv2023

Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current TNM or Veterans Administration Lung Study Group (VALG) staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent center, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggest potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better Progression Free Survival (PFS) and Overall Survival (OS) after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.

cancer biology↗