POU2F3 in SCLC: Clinicopathologic and Genomic Analysis With a Focus on Its Diagnostic Utility in Neuroendocrine-Low SCLC

Baine, Marina K.; Febres‐Aldana, Christopher A.; Chang, Jason C.; Jungbluth, Achim A.; Sethi, Shenon; Antonescu, Cristina R.; Travis, William D.; Hsieh, Min‐Shu; Roh, Mee Sook; Homer, Robert J.; Ladanyi, Marc; Egger, Jacklynn V.; Lai, W. Victoria; Rudin, Charles M.; Rekhtman, Natasha

doi:10.1016/j.jtho.2022.06.004

Cited by 47 publications

(78 citation statements)

References 45 publications

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“…According to the protein expression of NE and non‐NE markers described by Zhang et al., 7 as expected, SCLC‐A and ‐N cell lines showed NE features, whereas those in the SCLC‐P and ‐Y groups were associated with rather non‐NE protein profiles. This is in line with the results of a recent IHC‐based study on human tissue specimens, in which the authors also found that the likelihood of POU2F3 expression in SCLC is quantitatively linked with the level of NE marker expression and SCLC‐P tumours are characterized by the near‐complete absence of NE differentiation 64 . Therefore, including POU2F3 as a potential additional diagnostic marker might represent an appealing approach for the diagnosis of SCLC tumours that lack or exhibit minimal level of standard NE markers 64 .…”

Section: Discussionsupporting

confidence: 88%

“…64 Therefore, including POU2F3 as a potential additional diagnostic marker might represent an appealing approach for the diagnosis of SCLC tumours that lack or exhibit minimal level of standard NE markers. 64 Meanwhile, in another study, the same group also showed that the expression of conventional markers linked with NE differentiation is substantially higher in ASCL1-and NEUROD1defined tumours (vs. ASCL1/NEUROD1-double-negative tumours), which as well corresponds with our findings. 12 Regarding epithelial and mesenchymal traits, a study on SCLC cell lines 65 outlined that SCLC-P and -Y carry epithelial and mesenchymal attributes, respectively, whereas SCLC-A and -N subtypes have mixed characteristics.…”

Section: Discussionmentioning

confidence: 99%

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In‐depth proteomic analysis reveals unique subtype‐specific signatures in human small‐cell lung cancer

Szeitz

Woldmar

Valkó

et al. 2022

Clinical & Translational Med

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Background Small‐cell lung cancer (SCLC) molecular subtypes have been primarily characterized based on the expression pattern of the following key transcription regulators: ASCL1 (SCLC‐A), NEUROD1 (SCLC‐N), POU2F3 (SCLC‐P) and YAP1 (SCLC‐Y). Here, we investigated the proteomic landscape of these molecular subsets with the aim to identify novel subtype‐specific proteins of diagnostic and therapeutic relevance. Methods Pellets and cell media of 26 human SCLC cell lines were subjected to label‐free shotgun proteomics for large‐scale protein identification and quantitation, followed by in‐depth bioinformatic analyses. Proteomic data were correlated with the cell lines’ phenotypic characteristics and with public transcriptomic data of SCLC cell lines and tissues. Results Our quantitative proteomic data highlighted that four molecular subtypes are clearly distinguishable at the protein level. The cell lines exhibited diverse neuroendocrine and epithelial–mesenchymal characteristics that varied by subtype. A total of 367 proteins were identified in the cell pellet and 34 in the culture media that showed significant up‐ or downregulation in one subtype, including known druggable proteins and potential blood‐based markers. Pathway enrichment analysis and parallel investigation of transcriptomics from SCLC cell lines outlined unique signatures for each subtype, such as upregulated oxidative phosphorylation in SCLC‐A, DNA replication in SCLC‐N, neurotrophin signalling in SCLC‐P and epithelial–mesenchymal transition in SCLC‐Y. Importantly, we identified the YAP1‐driven subtype as the most distinct SCLC subgroup. Using sparse partial least squares discriminant analysis, we identified proteins that clearly distinguish four SCLC subtypes based on their expression pattern, including potential diagnostic markers for SCLC‐Y (e.g. GPX8, PKD2 and UFO). Conclusions We report for the first time, the protein expression differences among SCLC subtypes. By shedding light on potential subtype‐specific therapeutic vulnerabilities and diagnostic biomarkers, our results may contribute to a better understanding of SCLC biology and the development of novel therapies.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

In‐depth proteomic analysis reveals unique subtype‐specific signatures in human small‐cell lung cancer

Szeitz

Woldmar

Valkó

et al. 2022

Clinical & Translational Med

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“…Tuft cells have therefore been hypothesized as the cell of origin for this subtype of SCLC. It is important to note that tuft cells lack the expression of usual NE markers and therefore, SCLC-P tend to be NE low/- [ 57 ].…”

Section: Emerging Subtypes In Sclcmentioning

confidence: 99%

“…POU2F3, the novel transcriptional factor expressed in 7% of SCLC, is showing great promise as a diagnostic biomarker in NE low/- SCLCs. Baine et al analyzed POU2F3 IHC expression in SCLC (n = 123) and other major lung cancer types (n = 433) [ 57 ]. Expression was diffusely positive in 70% of SCLCs that were fully NE negative.…”

Section: Potential Clinical Utility Of Emerging Subtypesmentioning

confidence: 99%

Emerging Biomarkers and the Changing Landscape of Small Cell Lung Cancer

Keogh

Finn

Radonic

2022

Cancers

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Small cell lung cancer (SCLC) is a high-grade neuroendocrine malignancy with an aggressive behavior and dismal prognosis. 5-year overall survival remains a disappointing 7%. Genomically, SCLCs are homogeneous compared to non-small cell lung cancers and are characterized almost always by functional inactivation of RB1 and TP53 with no actionable mutations. Additionally, SCLCs histologically appear uniform. Thus, SCLCs are currently managed as a single disease with platinum-based chemotherapy remaining the cornerstone of treatment. Recent studies have identified expression of dominant transcriptional signatures which may permit classification of SCLCs into four biologically distinct subtypes, namely, SCLC-A, SCLC-N, SCLC-P, and SCLC-I. These groups are readily detectable by immunohistochemistry and also have potential predictive utility for emerging therapies, including PARPi, immune checkpoint inhibitors, and DLL3 targeted therapies. In contrast with their histology, studies have identified that SCLCs display both inter- and intra-tumoral heterogeneity. Identification of subpopulations of cells with high expression of PLCG2 has been linked with risk of metastasis. SCLCs also display subtype switching under therapy pressure which may contribute furthermore to metastatic ability and chemoresistance. In this review, we summarize the recent developments in the understanding of the biology of SCLCs, and discuss the potential diagnostic, prognostic, and treatment opportunities the four proposed subtypes may present for the future. We also discuss the emerging evidence of tumor heterogeneity and plasticity in SCLCs which have been implicated in metastasis and acquired therapeutic resistance seen in these aggressive tumors.

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“…In this issue, Baine et al 10 revealed that POU2F3 is specifically positive in a subset of basaloid squamous cell carcinomas (SCCs) that have morphologic similarities to SCLC and LCNEC. This new finding suggests a closer biological relationship between SCLC/LCNEC and basaloid SCC than is currently recognized and advances our understanding of the role of POU2F3 in tumor cells.…”

mentioning

confidence: 99%