PhD Scientific Days 2023

Pathology I.

NEM JELENT MEG Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer: an international multicenter study

Text of the abstract

Background: Lung cancer is still the leading cause of cancer-related mortality. Although our knowledge of small cell lung cancer (SCLC) molecular subtypes has grown significantly over the recent years, translating this information into clinics is still yet to come. Key transcription factors ASCL1, NEUROD1, POU2F3, and YAP1 have been recently reported to characterize uniquely different small cell lung cancer (SCLC) subtypes (SCLC-A; SCLC-N; SCLC-P; SCLC-Y). However, their clinical presence and therapeutic relevance have not yet been widely investigated.
Methods: Immunohistochemistry (IHC) was performed on surgically resected specimens of 386 SCLC patients. Furthermore, large-scale proteomic and in-depth bioinformatical analyses were also conducted in 26 human SCLC cell lines, and standard-of-care and targeted agents were used to evaluate distinct therapeutic vulnerabilities in vitro.
Results: Our results revealed SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), SCLC-P (POU2F3-dominant) and a cluster analysis also identified a quadruple-negative SCLC specific subtypes (SCLC-QN). The existence of YAP1-subtype SCLC was not confirmed. Interestingly, the highest overall survival rates were associated with non-neuroendocrine (SCLC-P and SCLC-QN) whereas the lowest were with neuroendocrine (SCLC-A, SCLC-N, SCLC-AN) subtypes. Proteomic pathway enrichment analysis identified unique expressional signatures for each SCLC subtype. Cell viability assays demonstrated remarkable sensitivity and resistance differences to standard-of-care chemotherapeutics and targeted agents between distinct SCLC subtypes.
Conclusions: Differential expression signatures of key transcription factors define different SCLC subtypes. IHC was not able to distinguish a separate YAP1-subtype SCLC. Our findings may contribute to a better insight into the biology of SCLC and reveal distinct vulnerability profiles defined by transcription regulators.

Funding: BF is a recipient of the Semmelweis 250+ Excellence PhD scholarship of Semmelweis University. BD, ZM, JF, KB, JM, ZL, NB, and SP acknowledge funding from the Hungarian National Research, Development, and Innovation Office (KH130356 and KKP126790 to BD; 2020-1.1.6-JÖVŐ and TKP2021-EGA-33 to BD, ZM, JF, and KB; NAP2-2017-1.2.1- NKP-00002 and K129065 to JM; OTKA #124652 and OTKA #129664 to ZL; ANN125583 to NB and SP). BD was also supported by the Austrian Science Fund (FWF I3522, FWF I3977 and I4677). VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. ZL was supported by the ESMO Translational Research Fellowship. ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary, and by the Hungarian Respiratory Society (MPA#2020) and is the recipient of the IASLC/ILCF Young Investigator Grant 2022.