bims-raghud 2025-08-24 papers

Issue of 2025–08–24
four papers selected by
Irene Sambri, TIGEM

Biochim Biophys Acta Mol Cell Res. 2025 Aug 15. pii: S0167-4889(25)00151-X. [Epub ahead of print] 120046

Calcium-dependent regulation of physiological vs pathological cardiomyocyte hypertrophy.

Joshua Chung, Nathan Isles, Stuart Johnston, David J Collins, Julie R McMullen, H Llewelyn Roderick, Vijay Rajagopal.

Cardiomyocyte hypertrophic growth contributes to the adaptative response of the heart to meet sustained increases in hemodynamic demand. While hypertrophic responses to physiological cues maintains or enhances cardiac function, when triggered by pathological cues, this response is maladaptive, associated with compromised heart function, although initially, this response maybe adaptive with preserved function. Since cues and activated pathways associated with both forms of hypertrophy overlap, the question arises as to the mechanism that determines these different outcomes. Here we evaluate the hypothesis that cardiomyocyte Ca2+ signalling - a regulator of pathological hypertrophy - also signals physiological hypertrophy. We discuss how different Ca2+ profiles, in distinct subcellular organelles/microdomains, and interacting with other signalling pathways, provide a mechanism for Ca2+ to be decoded to induce distinct hypertrophic phenotypes. We discuss how integration of computational with rich structural and functional cellular measurements can be used to decipher the role of Ca2+ in hypertrophic gene programming.

Keywords: Ca(2+) signalling; Cardiac hypertrophy; Cardiomyocyte; Computational modelling; IP(3) signalling

DOI: https://doi.org/10.1016/j.bbamcr.2025.120046

Sci Rep. 2025 Aug 17. 15(1): 30067

Transcriptionally up-regulation of CDKN1A/p21 by TFE3 fusion proteins worsened TFE3-rearranged renal cell carcinoma.

Yanwen Lu, Wenliang Ma, Yi Chen, Xiang Dong, Xinghe Pan, Lei Yang, Shuoming Zhou, Ning Liu, Dongmei Li, Weidong Gan.

The TFE3-rearranged renal cell carcinoma (TFE3-rRCC), which is an uncommon and aggressive form of kidney cancer, has an unfavorable prognosis. It has been shown that CDKN1A/p21 is high-expressed in TFE3-rRCC, however, the exact mechanism and the role of CDKN1A/p21 in TFE3-rRCC remain unclear. Our results indicated that the TFE3 fusions exacerbated TFE3-rRCC by transcriptionally upregulating CDKN1A/p21 expression. In terms of the mechanism, CDKN1A/p21 was a target gene of TFE3 fusions with positive regulation. Activation of AKT led to the cytoplasmic localization of highly expressed CDKN1A/p21, promoting TFE3-rRCC progression by anti-apoptosis and facilitating migration. Additionally, the remaining nuclear CDKN1A/p21 induced cellular senescence (CS) and secretion of senescence-associated secretory phenotype (SASP) factors, particularly IL-6 and IL-8, which recruited inhibitory immune cells and remodeled tumor microenvironment. This research presents that upregulation of CDKN1A/p21 transcriptionally by TFE3 fusions facilitates the progression of TFE3-rRCC by inducing anti-apoptosis, migration and CS, thus provides a promising target for treating TFE3-rRCC.

Keywords: CDKN1A/p21; Cellular senescence; SASP; TFE3 fusions; TFE3-rRCC

DOI: https://doi.org/10.1038/s41598-025-13302-x

Cell Biol Int. 2025 Aug 20.

Targeting mTOR and Its Associated Signaling to Induce Cell Death in Breast Cancer Stem Cells.

Kirti S Prabhu, Zahwa Mariyam, Syed A Rahman, Shilpa Kuttikrishnan, Fareed Ahmad, Ummu Habeeba, Abdul Q Khan, Afsheen Raza, Said Dermime, Salahddin A Gehani, Kulsoom Junejo, Shahab Uddin.

Breast cancer (BC) is a frequently diagnosed neoplasm in women and the second major cause of cancer-related deaths. Many BC patients develop metastasis and advanced tumors, increasing morbidity and mortality. There is substantial evidence that tumor relapses in BC patients are driven by a unique population of cells called cancer stem cells (CSCs). Breast CSCs confer stemness to BC and survive through the maintenance of several mechanisms, among which is the involvement of the mTOR signaling pathway. mTOR and its associated AKT signaling play a crucial role in regulating CSCsin various human cancers, including breast cancer. This study investigated the role of targeting mTOR/AKT signaling in the modulation of cell death in 2D and 3D breast cancer models. Torin-2, a dual mTOR inhibitor, effectively suppressed cell proliferation by inducing mitochondrial apoptosis. The inhibition of mTOR led to a decrease in AKT activity and downregulation of key translational machinery components, including 4EBP1, eIF4E, and p70S6K. Torin-2 treatment activated autophagy signaling in both 2D and 3D cell models. The induction of autophagy was evidenced by an increase in the autophagy protein LC3II/I in response to Torin-2 treatment. In addition, Torin-2 treatment of spheroids derived from breast cancer cells suppressed the expression of stem cell marker ALDH. Altogether, the dual inhibition of mTORC1 and mTORC2 by Torin-2 resulted in a more profound antitumor activity. This broader and more potent inhibition of the mTOR pathway contributes to effectiveness in suppressing 2D and 3D breast cancer cell growth and survival.

DOI: https://doi.org/10.1002/cbin.70071

Mol Oncol. 2025 Aug 17.

YAP1::TFE3 mediates endothelial-to-mesenchymal plasticity in epithelioid hemangioendothelioma.

Ant Murphy, Samuel Hartzler, Paula A Vargas Carranza, Shyaman Jayasundara, Madison E Yates, Nimod D Janson, Bozhi Liu, Annaleigh Benton, Majid Kazemian, Jason A Hanna.

The rare vascular sarcoma epithelioid hemangioendothelioma (EHE) is defined by WWTR1 or YAP1 gene rearrangements that result in functional fusion proteins. Previous studies have demonstrated the ability of these gene fusions to function as constitutively active TEAD coactivators, while also retaining the ability to drive transcription of canonical CAMTA1 or TFE3 genes, respectively. To better understand the biology underlying EHE, we generated EHE in vitro models using endothelial cell lines and found that inducible expression of YAP1::TFE3 (YT) caused a significant change in cellular plasticity. Specifically, YT expression led to endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells lose their highly specialized identity and gain expression of genes typically associated with mesenchymal cells. This plasticity is associated with anoikis resistance and increased migratory phenotypes. Notably, YT drives this phenotypic change independent of TEAD activity but requires dimerization and DNA binding domains encoded by the C-terminal TFE3 gene. Overexpression of TFE3 is insufficient to fully recapitulate the EndMT phenotypes driven by YT; implying that, although dispensable for EndMT, YAP-TEAD activity provides a meaningful contribution. This work supports a growing body of evidence that YT and WWTR1-CAMTA1 driven EHE may have distinct biological mechanisms, underscoring a potentially targetable oncogenic molecular dependency.

Keywords: EndMT; TFE3; YAP1; epithelioid hemangioendothelioma; rare cancer; vascular sarcoma

DOI: https://doi.org/10.1002/1878-0261.70112