<scp>NF‐κB</scp>‐dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells

Raynard, Clotilde; Ma, Xingjie; Huna, Anda; Tessier, Nolwenn; Massemin, Amélie; Zhu, Kexin; Flaman, Jean–Michel; Moulin, Florentin; Goehrig, Delphine; Médard, Jean-Jacques; Vindrieux, David; Treilleux, Isabelle; Hernández-Vargas, Héctor; Ducreux, Sylvie; Martin, Nadine; Bernard, David

doi:10.1111/acel.13632

Cited by 12 publications

(5 citation statements)

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“…Using a calcium chelator, we demonstrated that calcium activates STAT3 to promote EEC differentiation. Calcium-related signaling has previously been implicated in EEC differentiation in normal colon organoids and the Drosophila midgut, and neuroendocrine differentiation in breast and prostate cancer, suggesting that calcium signaling may generally drive neuroendocrine differentiation through STAT3 activation in normal and cancerous settings 20,[45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer

Ladaika,

Ghobashi,

Boulton

et al. 2024

Preprint

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Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

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Section: Discussionmentioning

confidence: 99%

Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer

Ladaika,

Ghobashi,

Boulton

et al. 2024

Preprint

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“…Cytosolic Ca 2+ experiments were achieved as previously described [ 39 ]. Briefly, plated cells were loaded with the Fura2-AM dye (2.5 µM; Molecular Probes) for 30 min at 37 °C in Ca 2+ -containing buffer (HBSS; Gibco).…”

Section: Methodsmentioning

confidence: 99%

Expression of the Calcium-Binding Protein CALB1 Is Induced and Controls Intracellular Ca2+ Levels in Senescent Cells

Raynard

Tessier

Huna

et al. 2022

IJMS

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In response to many stresses, such as oncogene activation or DNA damage, cells can enter cellular senescence, a state of proliferation arrest accompanied by a senescence-associated secretory phenotype (SASP). Cellular senescence plays a key role in many physiopathological contexts, including cancer, aging and aging-associated diseases, therefore, it is critical to understand how senescence is regulated. Calcium ions (Ca2+) recently emerged as pivotal regulators of cellular senescence. However, how Ca2+ levels are controlled during this process is barely known. Here, we report that intracellular Ca2+ contents increase in response to many senescence inducers in immortalized human mammary epithelial cells (HMECs) and that expression of calbindin 1 (CALB1), a Ca2+-binding protein, is upregulated in this context, through the Ca2+-dependent calcineurin/NFAT pathway. We further show that overexpression of CALB1 buffers the rise in intracellular Ca2+ levels observed in senescent cells. Finally, we suggest that increased expression of Ca2+-binding proteins calbindins is a frequent mark of senescent cells. This work thus supports that, together with Ca2+channels, Ca2+-binding proteins modulate Ca2+ levels and flux during cellular senescence. This opens potential avenues of research to better understand the role of Ca2+ and of Ca2+-binding proteins in regulating cellular senescence.

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“…Of note, breast and prostate non-hormone-dependent cancer cells do not enter into senescence and NED when exposed to the SASP. Nevertheless, co-occurrence of senescence and NED and whether it is restricted or not to hormone-dependent cells will have to be confirmed in different cellular models, and whether there are some interdependencies between these two phenotypes will need to be investigated ( Raynard et al, 2022 ).…”

Section: Senescent Cells Can Display Reinforcement Establishment and ...mentioning

confidence: 99%

Regulation of cell function and identity by cellular senescence

Huna,

Massemin,

Makulyte

et al. 2024

Journal of Cell Biology

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During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.

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NF‐κB‐dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells

Cited by 12 publications

References 50 publications

Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer

Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer

Expression of the Calcium-Binding Protein CALB1 Is Induced and Controls Intracellular Ca2+ Levels in Senescent Cells

Regulation of cell function and identity by cellular senescence

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