Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data

Rudin, Charles M.; Poirier, John T.; Byers, Lauren A.; Dive, Caroline; Dowlati, Afshin; George, Julie; Heymach, John V.; Johnson, Jane E.; Lehman, Jonathan M.; MacPherson, David; Massion, Pierre P.; Minna, John D.; Oliver, Trudy G.; Quaranta, Vito; Sage, Julien; Thomas, Roman K.; Vakoc, Christopher R.; Gazdar, Adi F.

doi:10.1038/s41568-019-0133-9

Cited by 734 publications

(934 citation statements)

References 65 publications

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“…One potential interesting facet of SCLC biology is the realization that it is not a homogenous disease; rather it is characterized by four different subtypes (16). The Rb lox/lox ; p130 lox/lox ; p53 lox/lox mouse model predominantly gives rise to the most prevalent subtype of SCLC, SCLC-A (17).…”

Section: Discussionmentioning

confidence: 99%

Sox2 is an oncogenic driver of small cell lung cancer

Voigt

Wollenzien

Feiner

et al. 2019

Preprint

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Although many cancer prognoses have improved in the past fifty years due to advancements in treatments, there has been little to no improvement in therapies for small cell lung cancer (SCLC) which currently has a five-year survival rate of less than 7%. One promising avenue to improve treatment for SCLC is to understand its underlying genetic alterations that drive its formation and growth. One such mutation in SCLC, which appears in many cancers, is of the Rb gene. When mutated, Rb causes hyperproliferation and loss of cellular identity. Normally Rb promotes differentiation by regulating lineage specific transcription factors including regulation of pluripotency factors such as Sox2. However, there is evidence that when certain tissues lose Rb, Sox2 becomes upregulated and promotes oncogenesis. To better understand the relationship between Rb and Sox2 and to uncover new treatments for SCLC we have studied the role of Sox2in Rb loss initiated tumors by investigating both the tumor initiation in SCLC genetically engineered mouse models, as well as tumor maintenance in SCLC cell lines.

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Section: Discussionmentioning

confidence: 99%

Sox2 is an oncogenic driver of small cell lung cancer

Voigt

Wollenzien

Feiner

et al. 2019

Preprint

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“…7D). Importantly, these clusters each contained mixtures of various SCLC subtypes based on the relative abundance of key transcription factors (24) (Supplementary Fig. S6).…”

Section: Human Sclcs Are Merged or Stratified By Different Classes Ofmentioning

confidence: 99%

“…Human SCLC requires loss of RB1 and TP53 (19,20)-two tumor suppressors that also developmentally restrict pluripotency (21,22). GEMMs with Rb1-Trp53 deleted by intratracheal delivery of Cre-expressing adenovirus (AdCMV-Cre) give rise to murine SCLCs similar to the classic ASCL1-high subtype of human SCLC (23,24). Deletion of additional tumor suppressors can synergize with Rb1-Trp53 loss (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

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

Schaff

Singh

Kim

et al. 2020

Preprint

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Small-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.

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“…NE-high is characterized by decreased immune cell infiltration defined as a cold or 'immune desert' phenotype, based on low levels of immune cell-related RNA expression. In contrast, NE-low was associated with tumors with increased immunogenicity, in other words 'hot' or 'immune oasis' phenotype (Calbo et al, 2011;George et al, 2015;McColl et al, 2017;Rudin et al, 2019). Consequently, NE-low SCLC patients may more likely respond to immunotherapies (Gazdar, 2018;Saito et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…SCLC is no longer considered as a single-disease entity, and subtypes are defined by distinct RNA gene expression profiles and can be classified into neuroendocrine (NE)-high and NElow tumors, which might have different immunogenicity (Rudin et al, 2019). NE-high is characterized by decreased immune cell infiltration defined as a cold or 'immune desert' phenotype, based on low levels of immune cell-related RNA expression.…”

Section: Introductionmentioning

confidence: 99%

Small Cell Lung Cancer Neuroendocrine Subtypes are Associated with Different Immune Microenvironment and Checkpoint Molecule Distribution

Dóra

Rivard

et al. 2020

Preprint

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The authors thank the patients and the clinical teams involved. We thank Leslie Rozeboom for her assistance in creating TMA blocks. ABSTRACTSmall cell lung cancer (SCLC) has recently been sub-categorized into neuroendocrine (NE)high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. We aimed to characterize the immune cell localization and the microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on FFPE TMAs with antibodies against CD45, CD3, CD8 and immune checkpoints including poliovirus receptor (PVR) and Indoleamine 2,3-dioxygenase (IDO).According to our results, the stroma was significantly more infiltrated by immune cells both in primary tumors and LN metastases (vs tumor cell nests). Immune (CD45+) cell density was significantly higher in tumor nests (110.6 ± 24.95 vs 42.74 ± 10.30, cell/mm2, p= 0.0048), with increased CD8+ effector T cell infiltration (21.81 ± 5.458 vs 3.16 ± 1.36 cell/ mm2, p < 0.001) in NE-low vs NE-high tumors. Furthermore, the expression of IDO was 3 confirmed on stromal and endothelial cells, and it positively correlated (r= 0.755, p<0.01) with higher immune cell density both in primary tumors and LN metastases, regardless of the NE pattern. Expression of IDO in tumor nests was significantly higher in NE-low (vs NEhigh) primary tumors. PVR expression was significantly higher in NE-low (vs NE-high) patients both in primary tumors) and LN metastases.To our knowledge, this is the first human study that demonstrates in situ that NE-low tumors are associated with increased immune cell infiltration compared to NE-high tumors. PVR and IDO are potential new targets in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.

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Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data

Cited by 734 publications

References 65 publications

Sox2 is an oncogenic driver of small cell lung cancer

Sox2 is an oncogenic driver of small cell lung cancer

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

Small Cell Lung Cancer Neuroendocrine Subtypes are Associated with Different Immune Microenvironment and Checkpoint Molecule Distribution

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