MUC1-C integrates aerobic glycolysis with suppression of oxidative phosphorylation in triple-negative breast cancer stem cells

Yamashita, Nami; Withers, Henry; Morimoto, Yoshihiro; Bhattacharya, Atrayee; Haratake, Naoki; Daimon, Tatsuaki; Fushimi, Atsushi; Nakashoji, Ayako; Thorner, Aaron R.; Isenhart, Emily; Rosario, Spencer; Long, Mark D.; Kufe, Donald

doi:10.1016/j.isci.2023.108168

Cited by 5 publications

(1 citation statement)

References 92 publications

(151 reference statements)

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“…Assessment of MUC1-C expression by IHC of TNBC core biopsies demonstrated staining in the cell membrane and cytoplasm [ 38 , 46 ]. MUC1-C is also expressed in the nucleus and localizes to chromatin [ 33 , 47 ]. Here, analysis of anti-MUC1-C nuclear precipitates from TNBC cells by mass spectroscopy identified the (i) NEAT1_2 FUS and RBM14 RBPs, and (ii) components of the BAF chromatin remodeling complex, SMARCC1, SMARCC2, ARID1A, SMARC4A/BRG1 and ARID1B that are integral to paraspeckles [ 9 , 25 ] (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression

Bhattacharya,

Wang,

Penailillo

et al. 2024

Oncogene

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The MUC1 gene evolved in mammals for adaptation of barrier tissues in response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA in response to loss of homeostasis. There is no known intersection of MUC1 with NEAT1 or paraspeckles. Here, we demonstrate that the MUC1-C subunit plays an essential role in regulating NEAT1 expression. MUC1-C activates the NEAT1 gene with induction of the NEAT1_1 and NEAT1_2 isoforms by NF-κB- and MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression of the SFPQ, NONO and FUS RNA binding proteins (RBPs) that associate with NEAT1_2 and are necessary for paraspeckle formation. MUC1-C integrates activation of NEAT1 and RBP-encoding genes by recruiting the PBAF chromatin remodeling complex and increasing chromatin accessibility of their respective regulatory regions. We further demonstrate that MUC1-C and NEAT1 form an auto-inductive pathway that drives common sets of genes conferring responses to inflammation and loss of homeostasis. Of functional significance, we find that the MUC1-C/NEAT1 pathway is of importance for the cancer stem cell (CSC) state and anti-cancer drug resistance. These findings identify a previously unrecognized role for MUC1-C in the regulation of NEAT1, RBPs, and paraspeckles that has been co-opted in promoting cancer progression.

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Section: Resultsmentioning

confidence: 99%

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression

Bhattacharya,

Wang,

Penailillo

et al. 2024

Oncogene

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FDFT1 maintains glioblastoma stem cells through activation of the Akt pathway

Mo,

Shao,

et al. 2024

Stem Cell Res Ther

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Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review

Serrano García,

Jávega,

Llombart Cussac

et al. 2024

Front. Immunol.

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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of progesterone and estrogen receptors and low (or absent) HER2 expression. TNBC accounts for 15-20% of all breast cancers. It is associated with younger age, a higher mutational burden, and an increased risk of recurrence and mortality. Standard treatment for TNBC primarily relies on cytotoxic agents, such as taxanes, anthracyclines, and platinum compounds for both early and advanced stages of the disease. Several targeted therapies, including bevacizumab and sunitinib, have failed to demonstrate significant clinical benefit in TNBC. The emergence of immune checkpoint inhibitors (ICI) has revolutionized cancer treatment. By stimulating the immune system, ICIs induce a durable anti-tumor response across various solid tumors. TNBC is a particularly promising target for treatment with ICIs due to the higher levels of tumor-infiltrating lymphocytes (TIL), increased PD-L1 expression, and higher mutational burden, which generates tumor-specific neoantigens that activate immune cells. ICIs administered as monotherapy in advanced TNBC yields only a modest response; however, response rates significantly improve when ICIs are combined with cytotoxic agents, particularly in tumors expressing PD-L1. Pembrolizumab is approved for use in both early and advanced TNBC in combination with standard chemotherapy. However, more research is needed to identify more potent biomarkers, and to better elucidate the synergism of ICIs with other targeted agents. In this review, we explore the challenges of immunotherapy in TNBC, examining the mechanisms of tumor progression mediated by immune cells within the tumor microenvironment, and the signaling pathways involved in both primary and acquired resistance. Finally, we provide a comprehensive overview of ongoing clinical trials underway to investigate novel immune-targeted therapies for TNBC.

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MUC1-C integrates aerobic glycolysis with suppression of oxidative phosphorylation in triple-negative breast cancer stem cells

Cited by 5 publications

References 92 publications

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression

FDFT1 maintains glioblastoma stem cells through activation of the Akt pathway

Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review

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