p53 deficient breast cancer cells reprogram preadipocytes toward tumor-protective immunomodulatory cells

The 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 breast tumors, undergo transcriptional, metabolic, and phenotypic reprogramming during breast cancer development and p...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 52; p. e2311460120
Main Authors:	Hassin, Ori, Sernik, Miriam, Seligman, Adi, Vogel, Felix C E, Wellenstein, Max D, Smollich, Joachim, Halperin, Coral, Pirona, Anna Chiara, Toledano, Liron Nomi, Caballero, Carolina Dehesa, Schlicker, Lisa, Salame, Tomer-Meir, Sarusi Portuguez, Avital, Aylon, Yael, Scherz-Shouval, Ruth, Geiger, Tamar, de Visser, Karin E, Schulze, Almut, Oren, Moshe
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 26-12-2023
Subjects:	Adipocytes Adipocytes - metabolism Adipose tissue Adipose Tissue - metabolism Biological Sciences Breast cancer Breast Neoplasms - pathology Deregulation Female Genes, p53 Humans Immune checkpoint Immunomodulation Inflammation Metabolism Missense mutation Myeloid cells p53 Protein PD-L1 protein Preadipocytes Stroma Therapeutic targets Tumor microenvironment Tumor Microenvironment - genetics Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors breast cancer preadipocytes adipocytes p53
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Summary:	The 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 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 inflammatory tumor microenvironment, including increased abundance of Ly6C+ and Ly6G+ myeloid cells and elevated expression of the immune checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 deregulation in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 dysfunction may promote cancer. Further elucidation of the interplay between p53 and adipocytes within the tumor microenvironment may suggest effective therapeutic targets for the treatment of breast cancer patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 1O.H., M.S., and A. Seligman contributed equally to this work. Contributed by Moshe Oren; received July 9, 2023; accepted November 17, 2023; reviewed by Guillermina Lozano and Carol Prives
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.2311460120