scholarly journals Abstract 2899: Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

2019 ◽  
Author(s):  
C. Allison Stewart ◽  
Carl M. Gay ◽  
Yuanxin Xi ◽  
Junya Fujimoto ◽  
Neda Kalhor ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Treatment Resistance ◽  
Small Cell ◽  
Intratumoral Heterogeneity ◽  
Small Cell Lung ◽  
Essential Component

scholarly journals Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer

Nature Cancer ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. 423-436 ◽  
Author(s):  
C. Allison Stewart ◽  
Carl M. Gay ◽  
Yuanxin Xi ◽  
Santhosh Sivajothi ◽  
V. Sivakamasundari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Therapy Resistance ◽  
Small Cell ◽  
Intratumoral Heterogeneity ◽  
Small Cell Lung

scholarly journals Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments

2020 ◽  
Author(s):  
Dylan L. Schaff ◽  
Shambhavi Singh ◽  
Kee-Beom Kim ◽  
Matthew D. Sutcliffe ◽  
Kwon-Sik Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Neuroendocrine Cells ◽  
Fluctuation Analysis ◽  
Alveolar Type ◽  
Small Cell Lung ◽  
Primary Tumors

AbstractSmall-cell lung cancers derive from pulmonary neuroendocrine cells, which have stemlike properties to reprogram into other cell types upon lung injury. It is difficult to uncouple the plasticity of these transformed cells from heritable changes that evolve in primary tumors or select in metastases to distant organs. Approaches to single-cell profiling are also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here, we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. Using labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of p53 and Rb, we profiled cell-to-cell transcriptional-regulatory heterogeneity in spheroid cultures and liver colonies seeded intravenously. Fluctuating transcripts in vitro were partly shared with other epithelial-spheroid models, and candidate heterogeneities increased considerably when cells were delivered to the liver. Colonization of immunocompromised animals drove the fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. We identified dozens of transcript heterogeneities that recur irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype. We conclude that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer.Statement of significanceThe single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease.

scholarly journals Morphological Subtypes of Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: Prognostic Heterogeneity and Its Underlying Mechanism

2021 ◽  
Vol 11 ◽  
Author(s):  
Huikang Xie ◽  
Hang Su ◽  
Erjia Zhu ◽  
Chang Gu ◽  
Shengnan Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Prospective Study ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tumor Spread ◽  
Specimen Handling ◽  
Spread Through Air Spaces

BackgroundTumor spread through air spaces (STAS) has three morphologic subtypes: single cells, micropapillary clusters, and solid nests. However, whether their respective clinical significance is similar remains unclear.MethodsWe retrospectively reviewed 803 patients with resected non-small cell lung cancer (NSCLC) from January to December 2009. Recurrence-free survival (RFS) and overall survival (OS) were compared among patients stratified by STAS subtypes. We also performed a prospective study of NSCLC resection specimens to evaluate the influence of a prosecting knife on the presence of STAS subtypes during specimen handling (83 cases).ResultsSTAS was found in 370 NSCLCs (46%), including 47 single cell STAS (13%), 187 micropapillary cluster STAS (50%), and 136 solid nest STAS (37%). STAS-negative patients had significantly better survival than patients with micropapillary cluster STAS (RFS: P < 0.001; OS: P < 0.001) and solid nest STAS (RFS: P < 0.001; OS: P < 0.001), but similar survival compared with those with single cell STAS (RFS: P = 0.995; OS: P = 0.71). Multivariate analysis revealed micropapillary cluster (RFS: P < 0.001; OS: P < 0.001) and solid nest STAS (RFS: P = 0.001; OS: P = 0.003) to be an independent prognostic indicator, but not for single cell STAS (RFS: P = 0.989; OS: P = 0.68). Similar results were obtained in subgroup analysis of patients with adenocarcinoma. The prospective study of NSCLC specimens suggested that 18 cases were considered as STAS false-positive, and most were singe cell pattern (13/18, 72%).ConclusionsSingle cell STAS was the common morphologic type of artifacts produced by a prosecting knife. A precise protocol of surgical specimen handling is required to minimize artifacts as much as possible.

Intratumoral heterogeneity and tumor evolution of small cell lung cancer through multi-regional sequencing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21103-e21103
Author(s):  
Yaxiong Zhang ◽  
Ningning Zhou ◽  
Huaqiang Zhou ◽  
Mengmeng Song ◽  
Pansong Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Intratumoral Heterogeneity ◽  
Postoperative Treatment ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Tumor Tissues

e21103 Background: Small cell lung cancer (SCLC) is a type of aggressive malignancy with poor prognosis, accounting for 15% of lung cancers. Intratumoral heterogeneity (ITH) has been investigated in lung adenocarcinoma or squamous cell carcinoma, but its role in SCLC still remains unclear. Exploring ITH and tumor evolution of SCLC is essential for its treatment and prognosis. Methods: 102 multi-regional tumor tissues were collected from 34 operative SCLC patients (pts) before systemic therapy during Sep. 2009 to Sep.2018 from Sun Yat-sen University Cancer Center. All of the enrolled cases were confirmed as SCLC by immunohistochemistry. We performed whole-exome sequencing (WES) of all the tumor tissues and assessed the ITH using clonal and subclonal somatic mutations or copy number variants. ITH was defined as the proportion of subclonal genetic alterations of all. The relationship between ITH and overall survival (OS) was also explored. Results: Among the enrolled 34 SCLC pts, the median age was 64 year. 28 pts had the smoking history. 23 pts received adjuvant therapy after surgery. Stage I-II and III-IV pts accounted for 50% respectively. The most frequent mutated genes were TP53 (88%), RB1 (70%), TTN (68%), TCEB3CL (65%), MUC16 (56%), and all of them were clonal. The median overall ITH was 0.36 (ranging from 0 to 1), while the mutational ITH and the CNV ITH were 0.50 (0.22 to 1) and 0.49 (0.22 to 1). Univariate analysis revealed that postoperative treatment (HR = 0.27, 0.07-0.97, p= 0.006) and higher CNV ITH (HR = 0.28, 0.08-0.99, p= 0.009) were significant positive predictors of OS, while higher mutational heterogeneity was not associated with OS (HR = 3.34, 0.91-12.25, p= 0.21) significantly. Conclusions: TP53, RB1, TTN, TCEB3CL and MUC16 were probably clonal mutations as early events in SCLC evolution. CNV ITH might be a prognostic predictor in SCLC, which should be verified in a large-sample cohort.

scholarly journals Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huaqiang Zhou ◽  
Yi Hu ◽  
Rongzhen Luo ◽  
Yuanyuan Zhao ◽  
Hui Pan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Exome Sequencing ◽  
Cell Lung Cancer ◽  
Disease Free Survival ◽  
Small Cell ◽  
Intratumoral Heterogeneity ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Mutation Distribution

AbstractSmall cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.

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