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P53 deficient breast cancer cells reprogram pre-adipocytes towards tumor protective immunomodulatory cells (WEA)

ABSTRACT: The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE238230 | GEO | 2024/07/01

REPOSITORIES: GEO

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p53 deficient breast cancer cells reprogram pre-adipocytes towards tumor protective immunomodulatory cells (WEP)

Project description:The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and of breast tumors, undergo transcriptional, metabolic and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an immunosuppressive tumor microenvironment, including increased abundance of myeloid-derived suppressor cells and elevated expression of the checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of several common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 loss in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 may act as a tumor suppressor. Further elucidation of the interplay between p53 mutations and adipocytes within the tumor microenvironment may suggest novel therapeutic targets for the treatment of breast cancer patients.

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SAA1-dependent reprogramming of adipocytes by tumor cells is associated with triple negative breast cancer aggressiveness

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Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53’s conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

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Downregulation of LATS kinases alters p53 to promote cell migration

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

Project description: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.

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Downregulation of LATS kinases alters p53 to promote cell migration

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Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer

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