A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity

Simpson, Kathryn; Stoney, Ruth; Frese, Kristopher K.; Simms, Nicole; Rowe, William; Pearce, Simon P.; Humphrey, Sam; Booth, Laura; Morgan, Derrick; Dynowski, Marek; Trapani, Francesca; Catozzi, Alessia; Revill, Mitchell; Helps, Thomas; Galvin, Melanie; Girard, Luc; Nonaka, Daisuke; Carter, Louise; Krebs, Matthew; Cook, Natalie; Carter, Mathew; Priest, Lynsey; Kerr, Alastair; Gazdar, Adi F.; Blackhall, Fiona; Dive, Caroline

doi:10.1038/s43018-020-0046-2

Cited by 128 publications

(178 citation statements)

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“…5 RNA sequencing (RNAseq) of 38 SCLC CTC-derived explants (CDXs) identified models representing three of the four consensus SCLC subtypes (ASCL1, NEU-ROD1, and POU2F3). 4 We discovered a further subtype on the basis of the expression of the neurogenic transcription factor (TF) ATOH1, 4 but our analysis did not reveal the YAP1 subtype. 4 Four studies collectively reported the rarity of the YAP1 subtype, in which YAP1 was expressed in five of 126 tumors and seven of 51 SCLC cell lines with low or absent NE marker expression, a low NE score, and a variant, loosely adherent morphology.…”

Section: Introductionmentioning

confidence: 67%

“…4 We discovered a further subtype on the basis of the expression of the neurogenic transcription factor (TF) ATOH1, 4 but our analysis did not reveal the YAP1 subtype. 4 Four studies collectively reported the rarity of the YAP1 subtype, in which YAP1 was expressed in five of 126 tumors and seven of 51 SCLC cell lines with low or absent NE marker expression, a low NE score, and a variant, loosely adherent morphology. [7][8][9][10] The tumor-suppressive Hippo pathway controls cell proliferation, apoptosis, and organ size.…”

Section: Introductionmentioning

confidence: 67%

“…4 CDX models were generated from patients' CTCs enriched from blood samples pre-chemotherapy baseline or at posttreatment disease progression time points (designated P or PP). 4 Transcriptomic analysis was performed with amendments to the previously described alignment (NFcore RNAseq pipeline with Spliced Transcripts Alignment to a Reference aligner) and annotation (mapped to eEnsembl version 99). 4 Three independent tumors per CDX were used for all analyses.…”

Section: Methodsmentioning

confidence: 99%

“…4 Transcriptomic analysis was performed with amendments to the previously described alignment (NFcore RNAseq pipeline with Spliced Transcripts Alignment to a Reference aligner) and annotation (mapped to eEnsembl version 99). 4 Three independent tumors per CDX were used for all analyses. Antibodies for IHC were the following: (1) YAP1 (1:100, ab52771; Abcam, Cambridge, United Kingdom); (2) REST (1:150, MA5-24606; ThermoFisher Scientific, Waltham, MA); and (3) SYP (pA0299; Leica Biosystems, Wetzlar, Germany).…”

Section: Methodsmentioning

confidence: 99%

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The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report

Pearsall

Humphrey

Revill

et al. 2020

Journal of Thoracic Oncology

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Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. Methods: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. Results: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYPpositive NE cells. Conclusions: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.

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Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report

Pearsall

Humphrey

Revill

et al. 2020

Journal of Thoracic Oncology

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“…Expression of PLGF in brain metastases is higher than in primary lung tumors from patients without brain metastases, which suggests that it could increase SCLC proclivity for brain metastasis (Li et al, 2013). As noted above, recent CDX models show metastatic potential to the brain in recipient mice (Table 1) (Simpson et al, 2020;Stewart et al, 2020); thus, these models may represent a new platform with which to investigate the molecular and cellular mechanisms of SCLC brain metastasis.…”

Section: Organ Tropismmentioning

confidence: 97%

Mechanisms of small cell lung cancer metastasis

2020

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Metastasis is a major cause of morbidity and mortality in cancer patients. However, the molecular and cellular mechanisms underlying the ability of cancer cells to metastasize remain relatively poorly understood. Among all solid tumors, small cell lung cancer (SCLC) has remarkable metastatic proclivity, with a majority of patients diagnosed with metastatic disease. Our understanding of SCLC metastasis has been hampered for many years by the paucity of material from primary tumors and metastases, as well as the lack of faithful pre-clinical models. Here, we review recent advances that are helping circumvent these limitations. These advances include methods that employ circulating tumor cells from the blood of SCLC patients and the development of diverse genetically engineered mouse models of metastatic SCLC. New insights into the cellular mechanisms of SCLC metastasis include observations of cell fate changes associated with increased metastatic ability. Ongoing studies on cell migration and organ tropism promise to expand our understanding of SCLC metastasis. Ultimately, a better molecular understanding of metastatic phenotypes may be translated into new therapeutic options to limit metastatic spread and treat metastatic SCLC.

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Tumor‐derived Vimentin as a novel biomarker for distinct subtypes predicting adjuvant chemotherapy resistance and T‐cell‐inflamed phenotype in small cell lung cancer

Deng,

Wang,

et al. 2023

MedComm

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Despite recent progress in subtype classification for small cell lung carcinoma (SCLC), little is known about the biomarker for triple‐negative (ASCL1, NEUROD1, and POU2F3 negative) tumors. The long‐term survival, adjuvant chemotherapy (ACT) response, and immune milieu in different SCLC subtypes have also not been well established. Here, we retrospectively collected a large cohort of 192 primary SCLC tumors and reported that ASCL1‐, NEUROD1‐ and POU2F3‐dominant subtypes counted for 61.38%, 19.31%, and 6.21%, respectively. Subtype intra‐tumoral heterogeneity and co‐expression at the single‐cell level existed substantially. The expression of tumor‐derived Vimentin (VIM) was nearly restricted to triple‐negative SCLC tumors (15/19, 78.9%) while YAP1 expression was distributed widely in other subtypes. The SCLC subtyping model was independently prognostic of OS and RFS (p < 0.001 and p = 0.043). In particular, patients with ASCL1‐positive SCLC tumors can benefit more from ACT, and VIM‐positive tumors did the opposite. Compared with other subtypes, the VIM‐dominant SCLC subtype was associated with abundant but functionally impaired CD4+ and CD8+ T‐cells, which highly expressed inhibitory checkpoints and potentially benefit from PD‐L1 blockade therapy. Our study showed that tumor‐derived SCLC‐V subtype could independently predict ACT response. The distinct immune landscape between subtypes may help inform personalized immune therapeutic approaches.

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A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity

Cited by 128 publications

References 75 publications

The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report

The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report

Mechanisms of small cell lung cancer metastasis

Tumor‐derived Vimentin as a novel biomarker for distinct subtypes predicting adjuvant chemotherapy resistance and T‐cell‐inflamed phenotype in small cell lung cancer

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