Adipocyte mesenchymal transition contributes to mammary tumor progression

Authors: ZHU, QINGZHANG - University Of Texas Southwestern Medical Center; ZHU, YI - Children'S Nutrition Research Center (CNRC); HEPLER, CHELSEA - University Of Texas Southwestern Medical Center; ZHANG, QIANBIN - University Of Texas Southwestern Medical Center; PARK, JIYOUNG - University Of Texas Southwestern Medical Center; GLINIAK, CHRISTY - University Of Texas Southwestern Medical Center; HENRY, GERVAISE - University Of Texas Southwestern Medical Center; CREWE, CLAIR - University Of Texas Southwestern Medical Center; BU, DAWEI - University Of Texas Southwestern Medical Center; ZHANG, ZHUZHEN - University Of Texas Southwestern Medical Center; ZHAO, SHANGANG - University Of Texas Southwestern Medical Center; MORLEY, THOMAS - University Of Texas Southwestern Medical Center; LI, NA - University Of Texas Southwestern Medical Center; KIM, DAE-SEOK - University Of Texas Southwestern Medical Center; STRAND, DOUGLAS - University Of Texas Southwestern Medical Center; DENG, YINGFENG - University Of Texas Southwestern Medical Center; ROBINO, JACOB - Oregon Health & Science University; VARLAMOV, OLEG - Oregon Health & Science University; GORDILLO, RUTH - University Of Texas Southwestern Medical Center; KOLONIN, MIKHAIL - University Of Texas Health Science Center; KUSMINSKI, CHRISTINE - University Of Texas Southwestern Medical Center; GUPTA, RANA - University Of Texas Southwestern Medical Center; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/23/2022
Publication Date: 9/13/2022
Citation: Zhu, Q., Zhu, Y., Hepler, C., Zhang, Q., Park, J., Gliniak, C., Henry, G.H., Crewe, C., Bu, D., Zhang, Z., Zhao, S., Morley, T., Li, N., Kim, D., Strand, D., Deng, Y., Robino, J.J., Varlamov, O., Gordillo, R., Kolonin, M.G., Kusminski, C.M., Gupta, R.K., Scherer, P.E. 2022. Adipocyte mesenchymal transition contributes to mammary tumor progression. Cell Reports. 40(11). Article 111362. https://doi.org/10.1016/j.celrep.2022.111362.
DOI: https://doi.org/10.1016/j.celrep.2022.111362

Interpretive Summary: In this paper, we discovered that certain fat cells change their identity when breast cancer spreads into the fat tissue. These transformed cells possess different metabolic states, act differently, and help the cancer cells grow. But, when we change the metabolism of these cells, we can slow down the growth of the breast cancer cells in our animal study. Additional studies are needed to better the association between fat and cancer cells.

Technical Abstract: Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment.