bims-pideca 2026-02-15 papers

Issue of 2026–02–15
four papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2523367123

ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation.

Navroop K Dhaliwal, Octavia Yifang Weng, Ai Tian, Aditi Aggarwal, Mai Ahmed, Guoria Sun, Afrin Bhattacharya, Wendy W Y Choi, Haruka Nishimura, Pragnya Chakraborty, Xiaoxue Dong, Yuncheng Wu, Michael D Wilson, Lu-Yang Wang, Luis F Parada, Julien Muffat, Yun Li.

Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors (NPs) and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including NP hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.

Keywords: PTEN; actin; human pluripotent stem cells; mTOR signaling; neurodevelopmental disorders

DOI: https://doi.org/10.1073/pnas.2523367123

Sci Signal. 2026 Feb 10. 19(924): eadr4063

Stabilization of IQGAP1 by the mTORC2 component PRR5 mediates mitogenic LINC01133-to-ERK signaling in triple-negative breast cancer.

Zhenbo Tu, Leah Moses, Yi Hu, Sworaj Sapkota, Liza M Quintana, Leismi Guerrero, George W Bell, Antoine E Karnoub.

Triple-negative breast cancers (TNBCs) lack targeted therapeutics that can inhibit their growth and progression. The long intergenic noncoding RNA LINC01133 promotes TNBC pathogenesis by increasing the abundance of proline-rich protein 5 (PRR5), an mTORC2 component that activates the kinase AKT in a PI3K-independent, mTORC2-dependent manner. Here, however, we found that TNBC cell proliferation was incompletely sensitive to AKT inhibitors alone because PRR5 also stimulated the mitogen-activated protein kinase (MAPK) cascade in an mTORC2-dependent manner. PRR5 associated with and prevented the ubiquitin-dependent proteasomal degradation of IQGAP1, an adaptor protein that promotes activation of the MAP kinase ERK. ERK signaling was essential for LINC01133-mediated TNBC proliferation in two- and three-dimensional cultures, and ERK inhibitors synergized with AKT blockade to suppress LINC01133-induced TNBC cell growth. Furthermore, PRR5 abundance was particularly enriched and correlated with that of phosphorylated ERK in samples from patients with TNBC. Our results highlight cross-talk between mTORC2 and ERK signaling downstream of LINC01133 and PRR5 that may be therapeutically targeted to treat TNBC.

DOI: https://doi.org/10.1126/scisignal.adr4063

Genes Dev. 2026 Feb 09.

Metabolic permissiveness: how tissue context shapes cancer.

Chrysanthi Moschandrea, Christian Frezza.

An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.

Keywords: cancer; metabolism; permissiveness

DOI: https://doi.org/10.1101/gad.353516.125

Stem Cell Reports. 2026 Jan 15. pii: S2213-6711(25)00384-4. [Epub ahead of print] 102780

Improving rigor and reproducibility through implementation of the ISSCR standards for human stem cell use in research.

Yvonne Fischer, Jack Mosher, Ivana Barbaric, Claudia Spits, Martin F Pera.

The International Society for Stem Cell Research (ISSCR) document "Standards For Human Stem Cell Use in Research" put forward a checklist for scientific journals to use in the assessment of compliance with its reporting standards. A trial implementation of this checklist at Stem Cell Reports revealed consistent gaps in the reporting of critical data relating to the cells and experimental methodologies employed in published manuscripts.

DOI: https://doi.org/10.1016/j.stemcr.2025.102780