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Spatial Transcriptome-Wide Profiling of Small Cell Lung Cancer Reveals Intra-Tumoral Molecular and Subtype Heterogeneity.

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid growth and early metastasis and is susceptible to treatment resistance and recurrence. Understanding the intra-tumoral spatial heterogeneity in SCLC is crucial for improving patient outcomes and clinically relevant subtyping. In this study, a spatial whole transcriptome-wide analysis of 25 SCLC patients at sub-histological resolution using GeoMx Digital Spatial Profiling technology is performed. This analysis deciphered intra-tumoral multi-regional heterogeneity, characterized by distinct molecular profiles, biological functions, immune features, and molecular subtypes within spatially localized histological regions. Connections between different transcript-defined intra-tumoral phenotypes and their impact on patient survival and therapeutic response are also established. Finally, a gene signature, termed ITHtyper, based on the prevalence of intra-tumoral heterogeneity levels, which enables patient risk stratification from bulk RNA-seq profiles is identified. The prognostic value of ITHtyper is rigorously validated in independent multicenter patient cohorts. This study introduces a preliminary tumor-centric, regionally targeted spatial transcriptome resource that sheds light on previously unexplored intra-tumoral spatial heterogeneity in SCLC. These findings hold promise to improve tumor reclassification and facilitate the development of personalized treatments for SCLC patients.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC11336901 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Spatial Transcriptome-Wide Profiling of Small Cell Lung Cancer Reveals Intra-Tumoral Molecular and Subtype Heterogeneity.

Zhang Zicheng Z Sun Xujie X Liu Yutao Y Zhang Yibo Y Yang Zijian Z Dong Jiyan J Wang Nan N Ying Jianming J Zhou Meng M Yang Lin L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240619 31

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid growth and early metastasis and is susceptible to treatment resistance and recurrence. Understanding the intra-tumoral spatial heterogeneity in SCLC is crucial for improving patient outcomes and clinically relevant subtyping. In this study, a spatial whole transcriptome-wide analysis of 25 SCLC patients at sub-histological resolution using GeoMx Digital Spatial Profiling technology is performed. This analysis ...[more]

PMID: 38896789

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Project description:Background: Studies in the past have identified selected immune cells that associate with different clinical outcomes in non-small cell lung cancer (NSCLC). Considering the fact that immune responses are heterogenous and that the clinical outcome could be influenced by the interplay of various immune cell types, it is imperative to evaluate multiple intra-tumoral immune cell types in the same set of patients. Objective: To evaluate the individual and combined effects of diverse intra-tumoral immune cell types on recurrence after complete surgical resection in early stage lung adenocarcinoma. Methods: We obtained NCBI GEO datasets for lung adenocarcinoma, the most prevalent histological subtype of NSCLC and re-analyzed the gene expression data of 292 patients with early stage cancer (IA/IB). CIBERSORT was used to resolve 22 immune cell types from the tumor transcriptomes. Survival analysis was carried out to assess the effect of immune cell types and genes associated with recurrence. Results: Out of the 22 cell types, a high proportion of Tregs and monocyte-macrophages in the tumors were associated with significantly increased probability of recurrence. Conversely, increased proportion of non-Treg CD4+ T cells and plasma cells were associated with a lower probability of recurrence. The higher expression of CCL20 (which can direct the migration of cells of B cell lineage), XCL1 (associated with prototypical Th1 responses) and the immunoglobulin chains IGHV4.34 and IGLV6.57 were associated with a significantly lower probability of recurrence. Importantly, the intra-tumoral immune phenotype comprising these four cell types varied among patients and differentially associated with recurrence depending on net levels of positive and negative prognostic factors. Despite a high level of intra-tumoral plasma cells, a concomitant high level of monocyte-macrophages reduced the freedom from recurrence from ~80 to ~50% at 80 months (p < 0.05). Furthermore, stratification of the patients on the basis of a score estimated from the levels of four cell types enabled the identification of patients with significantly increased probability of recurrence (~50%) after surgery. Significance: Our analysis suggests that concomitant levels of macrophages and plasma cells, in addition to the T regs and non-TregCD4+ T cells in tumors can identify patients with early stage lung cancer at greater risk of recurrence.

Project description:Intra-individual tumoral heterogeneity (ITH) is a hallmark of solid tumors and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian serous adenocarcinomas (OSAs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSA genomes using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumor lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSAs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes,. but common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSAs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both â??commonâ?? category and cancer-related genes were highly conserved in ascitic cells of OSAs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumor cells may serve as a potential resource to discover somatic mutations of primary OSA with diagnostic and therapeutic relevance. Genome wide DNA methylation profiling of ascitic cells as well as biopsies from ovarian serous adenocarcinomas cases obtained by Illumina Infinium 450k Human DNA methylation Beadchip Bisulphite converted DNA from the 16 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip

Dataset Information

Spatial Transcriptome-Wide Profiling of Small Cell Lung Cancer Reveals Intra-Tumoral Molecular and Subtype Heterogeneity.

Publications

Spatial Transcriptome-Wide Profiling of Small Cell Lung Cancer Reveals Intra-Tumoral Molecular and Subtype Heterogeneity.

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