PhD Scientific Days 2023

Budapest, 22-23 June 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

Bence Ferencz1,2, Zsolt Megyesfalvi1,2,3, Nandor Bárány2,3,4, András Lantos2, Zsuzsanna Valko2,3, Orsolya Pipek5, Christian Lang2, Anna Schwendenwein3, Felicitas Oberndorfer6, Sándor Paku4, Katalin Dezső4, János Fillinger2, Zoltán Lohinai2, Judit Moldvay2,7, Gabriella Gálffy8, Beáta Szeitz9, Melinda Rezeli10, Christopher Rivard11, Fred R Hirsch11,12, Luka Brcic13, Helmut Popper13, Izidor Kern14, Mile Kovacevic14, Jozef Skarda15,16, Marcel Mitták17, György Markó-Varga10, Krisztina Bogos2, Ferenc Rényi-Vámos1,2, Mir Alireza Hoda3, Thomas Klikovits3,18, Konrad Hoetzenecker3, Karin Schelch3, Viktoria Laszlo1,2,3*, Balazs Dome1,2,3,19*

1 Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
2 National Koranyi Institute of Pulmonology, Budapest, Hungary
3 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
4 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
5 Department of Physics of Complex Systems, Eotvos Lorand University, Budapest, Hungary
6 Department of Pathology, Medical University of Vienna, Vienna, Austria
7 MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Budapest, Hungary
8 Törökbálint County Institute of Pulmonology, Törökbálint, Hungary
9 Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
10 Department of Biomedical Engineering, Lund University, Lund, Sweden
11 Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
12 Tisch Cancer Institute, Center for Thoracic Oncology, Mount Sinai Health System, New York, NY, USA
13 Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
14 University Clinic for Respiratory and Allergic Diseases Golnik, Golnik, Slovenia
15 Institute of Clinical and Molecular Pathology, Medical Faculty, Palacky University Olomouc, Olomouc, Czech Republic
16 Department of Pathology, University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic
17 Department of Surgery, University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic
18 Department of Thoracic Surgery, Klinik Floridsdorf, Vienna, Austria
19 Department of Translational Medicine, Lund University, Lund, Sweden
* Shared last authors

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.