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Co-exposure to preadipocytes and Dioxin increase breast cancer cells aggressiveness through the generation of polynuclear giants cells.

ABSTRACT: Breast cancer (BC) is an important disease with high incidence as well as mortality among women, and critical socio-economic impacts. In the past 50 years, it has become a major health problem for women worldwide with over 2 million new cases diagnosed in 2018. This represents about 12% of all new cancer cases, 25% of all cancers in women and more than 600.000 cases of deaths worldwide in 2018 (Bray et al, 2018). If the cancer is located only in the breast, the 5-year relative survival rate of people with BC is 99% but this rate decreases if it is spread to lymph nodes (85%) and more dramatically if diagnosed with distant metastasis (26%) (Howlader et al, 2019; Siegel et al, 2017). Metastatic process, or the spread of tumor cells throughout the body, is responsible for about 90% of cancer patient deaths (Chaffer et al, 2011) and represents the central clinical challenge of solid tumor oncology. The development and progression of BC are complex processes that involve hormonal factors as well as numerous genetic and epigenetic alterations. During the past 10 years, many studies have focused on the role of the tumor microenvironment and the peritumoral stromal fraction, composed of adipose tissue, cancer-associated fibroblasts, endothelial cells and immune cells as macrophages and leukocytes. During tumor progression, cancer cells will deeply modify their microenvironment which in return will promote the growth and dissemination of the tumor (Allen et al, 2011; Polanska et al, 2013). Adipose tissue, consisting of mainly mature adipocytes and progenitors (preadipocytes and adipose-derived stem cells (ADSCs), is the most abundant component surrounding BC cells. Adipose tissue exerts a major endocrine and secretory role, and represents then an essential actor in the inflammatory, angiogenic or remodeling responses of the extracellular matrix, which influences tumor behavior.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Chiara guerrera

LAB HEAD: Chiara Guerrera

PROVIDER: PXD014328 | Pride | 2021-02-09

REPOSITORIES: Pride

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Project description:One of the greatest advances in therapy of estrogen receptor positive breast cancer has been the development of endocrine therapy. More than two thirds of primary breast tumors express estrogen receptor alpha (ERα) and their growth is mainly dependent on estrogen receptor activity. Several therapeutic approaches have thus been designed to inhibit ER activity in breast tissue. Tamoxifen, a selective ER modulator, is one of the main treatment options for premenopausal women with advanced ER positive breast cancer, and has also become well established as adjuvant therapy in the early breast cancer setting (Davies et al., 2011; Group, 1998; Jaiyesimi et al., 1995). In contrast to tamoxifen, which in other tissues such as bone and endometrium, can exert partial agonistic activity (Braithwaite et al., 2003; Fisher et al., 1994; Pietras, 2006), the selective ER downregulator, fulvestrant, is a potent ER antagonist. Binding of fulvestrant to ER inhibits receptor dimerization and nuclear uptake, prevents estrogen-response element binding and accelerates ER degradation (Dauvois et al., 1993; Dowsett et al., 2005; Fawell et al., 1990; Wakeling et al., 1991). Fulvestrant is approved for treatment of postmenopausal women with advanced breast cancer who have relapsed or progressed on first-line endocrine therapy (Howell et al., 2002; Osborne et al., 2002; Robertson et al., 2003). Estrogen deprivation by treatment with aromatase inhibitors (such as letrozole, anastrozole or exemestane) which block synthesis of estrogens is another effective therapy option in postmenopausal women (Bonneterre et al., 2000; Cuzick et al., 2010; Dowsett et al., 2010; Mouridsen et al., 2001; Nabholtz et al., 2000). The large majority of patients with ER+ breast cancer experience an initial response to endocrine therapy, however, in many of these patients, the disease subsequently progresses and eventually anti-estrogen therapy ceases to have effect. Biomarkers predicting response to estrogen deprivation and new alternative treatments targeting the pathways supporting estrogen independent growth are therefore urgently needed (Patani and Martin, 2014; Patani et al., 2013). In order to understand how tumors respond to withdrawal of their main growth signal, a comparison of molecular features of tumor before and during endocrine therapy is necessary, and the fate of individual cancer cell sub-clones should be monitored. Since studies of cellular dynamics are very difficult to perform with clinical material, we made use of a patient derived, estrogen dependent, orthotopically growing luminal-like primary breast cancer xenograft model (PDX) (Bergamaschi et al., 2009; Huuse et al., 2012). This PDX model is a representative model for luminal breast cancers as the molecular characteristics, cellular heterogeneity and estrogen dependency of the primary tumor are retained over many passages. Functionally different subpopulations of cancer cells were previously defined by expression of the markers CD24 and SSEA-4 in this model (Skrbo et al., 2014), and it is therefore a suitable model for comparison of cellular and molecular effects of estrogen deprivation and ER-signaling inhibition. In this study, a quantitative MS-based proteomic analysis using SILAC and a label-free approach were performed, aiming to map changes in protein expression induced by endocrine therapy. Inhibition of ER-signaling seemed to induce CD24 and SSEA-4 expression on residual tumor cells. Proteomic analysis revealed overexpression of enzymes involved in TCA cycle, oxidative phosphorylation and fatty acid beta-oxidation following endocrine treatment when compared to untreated tumors. These results indicated possible reprogramming of cell metabolism and utilization of aerobic respiration, i.e. oxidative phosphorylation, in response to endocrine therapy.

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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Co-exposure to preadipocytes and Dioxin increase breast cancer cells aggressiveness through the generation of polynuclear giants cells.

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