Abstract 2822: Heterogeneity of CD56+ circulating tumor cells and derived xenografts and response to treatment in small cell lung cancer
Authors: Martinetti Laëtitia , Montagne Pierre , Davilma Marlène , Jarry Ulrich , Chatziioannou Aristotelis , Aubry Marc , Ricordel Charles , Pedeux Rémy 
Published: March 2024

Abstract
Small cell lung cancer (SCLC) represents the most aggressive subtype of lung cancer, comprising 15% of all cases. Clinical advancements in SCLC have been hindered by slow progress, attributed to significant tumor heterogeneity and early metastasis. The majority of patients experience relapse within a few months post-treatment, with 20% exhibiting chemorefractory characteristics. Recent identification of molecular subtypes in SCLC, dependent on predominant transcription factors ASCL1, NEUROD1, and POU2F3, has opened avenues for potential therapeutic targets. Preliminary studies on these transcriptomic subtypes suggest distinct therapeutic susceptibilities, and intriguingly, chemotherapy may induce alterations in transcriptomic subtypes.In the context of SCLC, diagnosis reveals a substantial presence of circulating tumor cells (CTCs) in the patient's bloodstream, which can be efficiently isolated. A previously published method allowed us to isolate CD56+ CTCs with high specificity (Ricordel et al., 2023). Our overarching hypothesis posits a connection between chemosensitivity and the heterogeneity of CTCs, leading us to seek bioclinical markers predictive of chemotherapy response. The clinical study, named CTC-CPC, is a monocentric prospective non-interventional investigation involving treatment-naïve SCLC patients. Blood samples were collected at the time of diagnosis for subsequent analysis. In our study, whole exome sequencing data from isolated CD56+ CTCs of 22 SCLC patients were analyzed. Various methods were employed to characterize inter-tumoral heterogeneity, including the identification of genetic alterations (SSMs and Indels), mutational signatures, and disrupted pathways. Prominently affected pathways included ECM organization, axon guidance, Rho GTPases, and Wnt signaling. Additionally, we unveiled substantial intra-tumoral heterogeneity using PhyloWGS, a technique for reconstructing subclonal composition and evolution from tumor sample sequencing. To further explore the impact of treatment, we aimed to clarify the expression of ASCL1, NEUROD1, and POU2F3 transcription markers in xenografts generated from patient CTCs at the time of diagnosis. Immunohistochemical studies were performed to identify potential changes in molecular subtypes at the protein level. The molecular subtypes of the four CDX we generated were characterized, revealing heterogeneity in the intratumoral expression of transcription markers for some xenografts. Subsequently, CTC-derived xenografts were subjected to chemotherapy, with observations indicating a change in the number of cells positive for ASCL1 and NEUROD1 after treatment, particularly in the CEM51.01 line treated with carboplatin, suggesting a potential modification in the tumor subtype induced by the treatment
Citation Format: Laëtitia Martinetti, Pierre Montagne, Marlène Davilma, Ulrich Jarry, Aristotelis Chatziioannou, Marc Aubry, Charles Ricordel, Rémy Pedeux. Heterogeneity of CD56+ circulating tumor cells and derived xenografts and response to treatment in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2822.