POU2F3, also known as SKN-1a/OCT-11, is a transcription factor. It serves as a master regulator in a tuft cell-like variant of small cell lung cancer (SCLC), defining a special molecular subtype of SCLC known as SCLC-P [4]. It has been found to be associated with a chemosensory lineage of cells, and its expression is mutually exclusive of ASCL1 and NEUROD1 in SCLC [1]. Genetic models could potentially offer insights into its regulatory mechanisms and functions.

In SCLC, POU2F3-positive tumors represent a distinct neuroendocrine-low subtype. POU2F3 is expressed in about 7%-13.41% of SCLC cases, strongly associated with low expression of standard neuroendocrine markers [1,2,3]. SCLC-P exhibits unique genomic alterations, such as PTEN inactivation, MYC amplifications, and 20q13 amplifications, yet similar rates of RB1 and TP53 alterations as other SCLC [2]. Additionally, in POU2F3-positive SCLCs, the mammalian SWI/SNF (mSWI/SNF) complex has been identified as a top dependency for POU2F3 expression and SCLC proliferation, and disruption of its activity can attenuate tumor growth [5]. Outside of SCLC, POU2F3 expression is limited to some large cell neuroendocrine carcinomas and basaloid squamous cell carcinomas [2].

In conclusion, POU2F3 is a key determinant in a tuft cell-like variant of SCLC, defining a distinct neuroendocrine-low subtype with unique genomic features. The study of POU2F3 in SCLC through various research models, especially those targeting its associated dependencies like the mSWI/SNF complex, may provide new therapeutic strategies for this disease.

References:

1. Baine, Marina K, Hsieh, Min-Shu, Lai, W Victoria, Rudin, Charles M, Rekhtman, Natasha. 2020. SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization. In Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 15, 1823-1835. doi:10.1016/j.jtho.2020.09.009. https://pubmed.ncbi.nlm.nih.gov/33011388/

2. Baine, Marina K, Febres-Aldana, Christopher A, Chang, Jason C, Rudin, Charles M, Rekhtman, Natasha. 2022. POU2F3 in SCLC: Clinicopathologic and Genomic Analysis With a Focus on Its Diagnostic Utility in Neuroendocrine-Low SCLC. In Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 17, 1109-1121. doi:10.1016/j.jtho.2022.06.004. https://pubmed.ncbi.nlm.nih.gov/35760287/

3. Wang, Yue, Jin, Yan, Shen, Xuxia, Lin, Yicong, Li, Yuan. 2023. POU2F3: A Sensitive and Specific Diagnostic Marker for Neuroendocrine-low/negative Small Cell Lung Cancer. In The American journal of surgical pathology, 47, 1059-1066. doi:10.1097/PAS.0000000000002081. https://pubmed.ncbi.nlm.nih.gov/37357936/

4. Huang, Yu-Han, Klingbeil, Olaf, He, Xue-Yan, Shi, Junwei, Vakoc, Christopher R. 2018. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. In Genes & development, 32, 915-928. doi:10.1101/gad.314815.118. https://pubmed.ncbi.nlm.nih.gov/29945888/

5. Duplaquet, Leslie, So, Kevin, Ying, Alexander W, Kadoch, Cigall, Oser, Matthew G. 2024. Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer. In Cancer cell, 42, 1352-1369.e13. doi:10.1016/j.ccell.2024.06.012. https://pubmed.ncbi.nlm.nih.gov/39029464/