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Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [Proximal_and_Distal-RNA-seq]

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid progression and a poor prognosis. The perineural invasion (PNI) phenomenon is prevalent in SCLC and represents a critical clinical-pathological feature; nevertheless, the mechanisms and its influence on disease progression and patient survival remain unclear. In this study, we established PNI as an independent adverse prognostic factor of SCLC based on surgical cohort evidence. We further demonstrated that the neural microenvironment upregulates STMN2, a neuron-specific microtubule-destabilizing protein, in SCLC cells. Mechanistically, STMN2 activates the β-alanine metabolic pathway in a concentration-dependent manner, leading to increased intracellular β-alanine levels and thereby enhancing tumor cell migration and invasion. In vivo experiments confirmed that STMN2 knockdown significantly suppresses neural invasion in SCLC, an effect reversible upon exogenous β-alanine supplementation. Together, these findings identify a neural-STMN2-β-alanine-invasion axis in SCLC. This work not only provides novel mechanistic insights into neural invasion but also highlights a promising therapeutic target for countering PNI, underscoring its substantial translational relevance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322516 | GEO | 2026/03/09

REPOSITORIES: GEO

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Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [beta-alanine-RNAseq]

Project description:Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid progression and a poor prognosis. The perineural invasion (PNI) phenomenon is prevalent in SCLC and represents a critical clinical-pathological feature; nevertheless, the mechanisms and its influence on disease progression and patient survival remain unclear. In this study, we established PNI as an independent adverse prognostic factor of SCLC based on surgical cohort evidence. We further demonstrated that the neural microenvironment upregulates STMN2, a neuron-specific microtubule-destabilizing protein, in SCLC cells. Mechanistically, STMN2 activates the β-alanine metabolic pathway in a concentration-dependent manner, leading to increased intracellular β-alanine levels and thereby enhancing tumor cell migration and invasion. In vivo experiments confirmed that STMN2 knockdown significantly suppresses neural invasion in SCLC, an effect reversible upon exogenous β-alanine supplementation. Together, these findings identify a neural-STMN2-β-alanine-invasion axis in SCLC. This work not only provides novel mechanistic insights into neural invasion but also highlights a promising therapeutic target for countering PNI, underscoring its substantial translational relevance.

2026-03-09 | GSE322515 | GEO

Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [beta-alanine-RNAseq]

Project description:Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [beta-alanine-RNAseq]

| PRJNA1430256 | ENA

Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation [RNA-seq]

Project description:Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. Despite its recognized clinical impact, the molecular mechanisms underlying PNI are not well understood. In this study, we isolated perineural invasion-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Utilizing single-cell, high-throughput sequencing, and metabolomics, we identified a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAFs-derived lactate is absorbed by tumor cells, facilitating histone H3K18 lactylation. This epigenetic modification activates the transcription of neural invasion-associated genes such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibits neural invasion in a KPC mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Our findings provide critical insights into the role of pCAFs in the PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.

2025-03-05 | GSE290845 | GEO

Cancer-Associated Fibroblasts Shape a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer via Histone Lactylation

2025-03-19 | GSE290654 | GEO

Transcription profiling of human neuro-invasive pancreatic tumors engineered in-vitro compared to less invasive parental cells

Project description:Perineural invasion (PNI) is considered to be a specific path for the spread of pancreatic cancer cells and PNI is thought to be one of the important factors that determine local recurrence after resection. In addition PNI has been implicated in the pain syndrome that affects the majority of pancreatic ductal adenocarcinoma (PDAC) patients. Here we aimed to investigate the transcriptional differences between neuro-invasive tumors engineered in-vitro compared to less invasive parental cells. Two colour differential hybridisations were performed with human universal reference total RNA (Clontech, #636538).

2009-04-01 | E-TABM-400 | biostudies-arrayexpress

Gene expression signatures associated with Perineural Invasion in pancreatic ductal adenocarcinoma

Project description:Perineural invasion (PNI) is a prominent characteristic of pancreatic ductal adenocarcinoma (PDAC) and indicates poor prognosis. The invasion of the surrounding nerves by pancreatic cancer cells not only provides route for metastasis but also contributes to neural remodeling and changes in the neuronal milieu that can profoundly influenced the microenvironment of pancreatic cancer. To investigate the downstream molecules associated with PNI, the experiment analyzed mRNA expression of 50 pairs of pancreatic ductal adenocarcinoma tissue and paired adjacent non-tumor tissue, among which 28 pairs of cases diagnosed with PNI by experienced pathologist. Results provide new insight into molecular basis for the influence of PNI on the microenvironment of pancreatic cancer.

2017-08-04 | GSE102238 | GEO

Molecular characterization of perineural invasion-competent cancer cells using a novel in vitro model

Project description:Invasion of cancer cells into peripheral nerves, known as perineural invasion (PNI), is an established risk factor for cancer recurrence and metastasis. However, there are no approaches available to specifically target PNI-competent cancer cells for diagnostic and therapeutic purposes. The lack of ideal preclinical models simulating natural PNI challenges the true characterization of PNI cells and understanding of the cellular events underlying PNI. In this work, we developed an in vitro model recapitulating the biological events associated with natural PNI. The novel in vitro model included intact nerve preparations in 3D culture format to facilitate natural PNI. Using the novel model, we found that autonomic neurosignaling promotes PNI demonstrating the utility of this model in exploring the fundamental biology of PNI. Using this model, we also demonstrated that PNI cells have survival advantages against cancer chemotherapy further demonstrating the utility of this model in screening potential anti-PNI therapies. We also characterized the molecular profile of PNI-competent breast cancer cells purified from the in vitro model. Follow-up analysis showed that CPLANE1 and hemopexin are potential markers of PNI cells for future theranostics purposes. Overall, this work presents a new in vitro model of PNI, which can be used to study the fundamentals of PNI and screen potential anti-PNI therapies.

2025-07-14 | PXD059147 | Pride

Expression of microRNAs and Protein-coding Genes Associated with Perineural Invasion in Prostate Cancer

Project description:BACKGROUND. Perineural invasion (PNI) is the dominant pathway for local invasion in prostate cancer. To date, only few studies have investigated the molecular differences between prostate tumors with PNI and those without it. METHODS. To evaluate the involvement of both microRNAs and protein-coding genes in PNI, we determined their genome-wide expression with a custom microRNA microarray and Affymetrix GeneChips in 50 prostate adenocarcinomas with PNI and 7 without it. In-situ hybridization and immunohistochemistry was used to validate candidate genes. RESULTS. Unsupervised classification of the 57 adenocarcinomas revealed two clusters of tumors with distinct global microRNA expression. One cluster contained all non-PNI tumors and a subgroup of PNI tumors. Significance analysis of microarray data yielded a list of microRNAs associated with PNI. At a false discovery rate (FDR) < 10%, 19 microRNAs were higher expressed in PNI tumors than in non-PNI tumors. The most differently expressed microRNA was miR-224. In-situ hybridization showed that this microRNA is expressed by perineural cancer cells. The analysis of protein-coding genes identified 34 transcripts that were differently expressed by PNI status (FDR <10%). These transcripts were down-regulated in PNI tumors. Many of those encoded metallothioneins and proteins with mitochondrial localization and involvement in cell metabolism. Consistent with the microarray data, perineural cancer cells tended to have lower metallothionein expression by immunohistochemistry than nonperineural cancer cells. CONCLUSIONS. Although preliminary, our findings suggest that alterations in microRNA expression, mitochondrial function, and cell metabolism occur at the transition from a non-invasive prostate tumor to a tumor with PNI. Keywords: Disease State analysis

2008-07-01 | GSE7055 | GEO

Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [Proximal_and_Distal-RNA-seq]

Project description:Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [Proximal_and_Distal-RNA-seq]

| PRJNA1430247 | ENA

Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer [mRNA-seq]

Project description:Lactylation, a metabolic stress-induced modification, plays a pivotal role in regulating diverse biological processes. Its involvement in perineural invasion (PNI) of pancreatic ductal adenocarcinoma (PDAC), however, has not been clearly defined. Our study demonstrates that patients with severe PNI exhibit significantly elevated levels of global lactylation and lactate, correlating with poorer prognosis. We identified NSUN2, a methyltransferase, as a crucial mediator of lactylation-driven PNI. Inhibition of lactylation or NSUN2 markedly reduced the neural infiltration capabilities of tumor cells. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC11 mRNA, enhanced their mRNA stability. Consistently, analyses using a KPC mouse model demonstrated that the lactylation of NSUN2/CDCP1/STC11 axis enhanced PNI through m5C modification. Our findings reveal that lactylation-driven NSUN2-mediated RNA m5C modification plays a pivotal role in promoting PNI and suggest that targeting NSUN2 could offer a promising therapeutic strategy for PDAC.

2025-06-15 | GSE299600 | GEO

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