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The transcriptome of highly aneuploid senescent cells reveals interaction with the tumor microenvironment and a pro-survival role of Yorkie

ABSTRACT: Chromosomal instability (CIN), an increased rate of changes in chromosome structure and number, is observed in most human carcinomas. Drosophila epithelial tumor models have been instrumental in demonstrating that, beyond the generation of genomic copy number heterogeneity, CIN can act as a source of tumor growth, metastasis and malignancy through the production of aneuploidy-induced senescent cells. Here we characterized the transcriptional program of these cells. We present evidence that most cellular responses to aneuploidy and senescence, such as cell cycle arrest, autophagy induction, activation of the actin cytoskeleton and upregulation of genes involved in secretion, are reflected at the transcriptional level. Besides those secreted proteins mediating tumor growth, metastasis and malignancy, we unravel a role of Upd1 cytokine in driving the death of the nearby tumor microenvironment through activation of the JAK/STAT pathway and induction of autophagy. We also demonstrate a pro-survival role of the hippo-Yorkie pathway in tumor cells. Our data contribute to the identification of potential therapeutic strategies to block CIN-induced tumorigenesis by targeting senescent cells and blocking their ability to interact with the tumor microenvironment.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE306996 | GEO | 2026/05/07

REPOSITORIES: GEO

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Project description:Chromosomal instability (CIN), defined as an increased occurrence of chromosome segregation errors during cell division, is a prominent form of genomic instability (Bakhoum and Avi Landau, 2017). It is the major cause of aneuploidy, an imbalanced complement of whole chromosomes or chromosome arms, which is the most prevalent genetic alteration in human cancers (Vasudevan et al., 2021; Santaguida and Amon, 2015). Importantly, aneuploidy is commonly associated with ongoing CIN through consecutive cell divisions (Shelzer et al. 2011; Passerini et al., 2016), resulting in intratumor genetic heterogeneity, a central driver of cancer evolution and therapeutic resistance (Sansregret et al., 2018; Ben-David and Amon, 2019). Indeed, aneuploidy has been shown to act both as a tumor suppressor and as a tumor initiator (Weaver et al., 2007; Silk et al., 2013; Vasudevan et al., 2020), most likely depending on the specific chromosomes that are gained or lost (Ben-David et al., 2011; Sack et al., 2018; Adell et al., 2023). Despite the ubiquitous presence of CIN in several aneuploid cancer types and its clinical relevance, its presence in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored owing to the impaired proliferation of leukemic cells in vitro and the lack of reliable experimental models to comprehensively assess chromosome segregation in vivo. B-ALL is the most frequent childhood cancer, with 75% of cases occurring in children under 6 years of age, and it is characterized by the accumulation of highly proliferative immature B-cell precursors in the bone marrow (BM) (Hunger and Mullighan, 2015). The presence of CIN and its contribution to aneuploid cB-ALL progression is largely unknown due to the lack of preclinical models to study actively dividing cells. Accordingly, studies of CIN in cB-ALL are limited to the characterization of chromosomal copy-number heterogeneity (chr-CNH) in primary cB-ALL samples, but there is controversy over its presence due to the different techniques used to assess karyotype variability (Raimondi et al., 1996; Talamo et al., 2010; Alpar et al., 2014; Heerema et al.; 2007; Ramos-Muntada et al., 2022). Here, we explored the presence and the levels of CIN in different clinically-relevant aneuploid subtypes of cB-ALL using single-cell whole-genome sequencing (WGS) of primary samples to reliably assess chr-CNH, and by generating a large cohort of PDX models from primary cB-ALL samples (cB-ALL-PDX). Our results in cB-ALL-PDX models revealed variable levels of CIN in aneuploid cB-ALL subtypes, which significantly correlate with intraclonal karyotype heterogeneity and with disease progression. Additionally, mass-spectrometry analyses of cB-ALL-PDX samples revealed a CIN “signature” enriched in mitosis and chromosome segregation regulatory pathways. We speculate that this signature identifies adaptive mechanisms to ongoing CIN in aneuploid cB-ALL cells, which displayed a transcriptional signature characterized by an impaired mitotic spindle as observed by RNA-sequencing (RNA-Seq) analyses of a large cohort of primary cB-ALL patient samples. Our work might help to improve stratification of patients with cB-ALL with different levels of CIN who could benefit in the future from new therapeutic approaches aiming to target ongoing CIN.

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The transcriptome of highly aneuploid senescent cells reveals interaction with the tumor microenvironment and a pro-survival role of Yorkie

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