bims-pideca 2026-08-09 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–08–09
nine papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

A Rac-PI3Kβ feedback loop drives GPVI-dependent platelet activation.
Mechanisms and Manifestations of Ligand Bias in Signaling: Focus on Receptor Tyrosine Kinases.
Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma.
Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia.
A tumour-derived organoid biobank maps cancer gene dependencies.
What's in a niche? Elucidating the role of the ECM in cell fate commitment.
A dependency map enhanced with next-generation 3D cancer models.
The Virtual Tissues foundation model resolves spatial proteomics across scales.
Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling.

iScience. 2026 Aug 21. 29(8): 116698

A Rac-PI3Kβ feedback loop drives GPVI-dependent platelet activation.

Tom N Durrant, James L Hutchinson, Carl J May, Justin S Trory, Samantha F Moore, Ingeborg Hers.

  Class I PI3Kβ is critical in controlling platelet activation and preserving thrombus stability under high shear. PI3Kβ is unique among class I phosphoinositide 3-kinases (PI3Ks) in being activated by Rho-family GTPases Rac and Cdc42, positioning it as a potential key link between Rho-family GTPases and platelet signaling. Here, we combined pharmacological inhibition with genetic approaches to define a direct Rho-PI3Kβ signaling axis in mouse platelets. Platelets from knockin mice carrying two point mutations within the Rho-binding domain (RBD) of the PI3Kβ catalytic subunit p110β exhibited impaired GPVI-mediated platelet signaling, functional responses, and spreading on fibrinogen. Pharmacological inhibition with the PI3Kβ-selective inhibitor AZD6482 demonstrated that these responses largely depend on the p110β RBD. Inhibition of Rac/Cdc42 in wild-type platelets phenocopied the knockin defects, supporting a direct role for Rho GTPases in PI3Kβ activation. Conversely, Rac activation was impaired in RBD-mutant and AZD6482-treated platelets, revealing a Rac-PI3Kβ feedback loop that amplifies GPVI-dependent platelet activation.

Keywords:  CCD42; GEF; GPVI; PI3,4,5P3; PI3Kβ; Rac; collagen; platelets

DOI:  https://doi.org/10.1016/j.isci.2026.116698
Chem Rev. 2026 Jul 30.

Mechanisms and Manifestations of Ligand Bias in Signaling: Focus on Receptor Tyrosine Kinases.

Ryan J Schuck, Tanaya Roy, Ana-Nicoleta Bondar, Pavel Krejci, Kalina Hristova.

The development of organisms and the maintenance of tissue homeostasis depend on complex intercellular signaling networks that govern basic cell functions. Because cells are typically exposed to many diverse ligands simultaneously, distinct intracellular mechanisms of cell signaling have evolved, allowing cells to accurately sense and respond to their environment. Here, we discuss the concept of ligand bias, which describes the ability of different ligands to preferentially activate specific signaling pathways, and thus produce divergent responses through the same receptor. Although bias can be challenging to identify and quantify, protocols have been established to (i) determine whether preferences exist and (ii) quantify these preferences. We review these protocols and their utility in studies of signaling by RTKs, the largest family of single-pass membrane receptors. We summarize the literature suggesting that RTKs engage in biased signaling and discuss the utility of signaling bias in therapeutics design. We discuss parallels with GPCR biased signaling, and lessons that have been learned after years of GPCR signaling research. Finally, we propose that RTK ligand bias appeared in evolution to diversify the morphogen signaling pathways that direct the development of tissues and organs in the mammalian body.

DOI: https://doi.org/10.1021/acs.chemrev.6c00023
J Clin Invest. 2026 Aug 06. pii: e206334. [Epub ahead of print]

Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma.

Chen Zhang, Xiaojuan Chao, Sha Neisha Williams, Xiaoli Wei, Anthony DiGirolamo, Alisha Bajracharya, Lichun Ma, Ming Huang, Nicholas Dunn, Wanqing Liu, Kaito Ueda, Masayuki Sugimoto, Andrea Ballabio, Hong-Min Ni, Wen-Xing Ding.

  Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific Tsc1 knockout (L-Tsc1 KO) and L-Tsc1,Tfeb double KO (DKO) mice. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1 KO mice showed increased hepatocyte plasticity, decreased HFN4α, increased YAP1 activation, and spontaneous HCC with increased SOX9 and CK19-positive biliary epithelial cell (BEC)-like cells at 8-12 months. Deletion of Tfeb dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-Tsc1 KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to non-canonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC. .

Keywords:  Autophagy; Cell biology; Hepatology; Liver cancer; Oncology

DOI:  https://doi.org/10.1172/JCI206334
Elife. 2026 Aug 06. pii: RP106893. [Epub ahead of print]14

Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia.

Amrapali Datta, Phanindra Dewan, Aswin Anto Puthoor, Tanya Chhabra, Tanishq Tejaswi, Sindhu Muthukrishnan, Akshar Rao, Sumantra Sarkar, Medhavi Vishwakarma.

  Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions between newly transformed and wild-type cells are critical in determining survival and growth of HRasV12 mutants in human mammary and bronchial epithelia, producing contrasting outcomes in the two tissues. In mammary epithelium, isolated mutants are extruded - typical of epithelial defense against cancer - while mutant groups become spatially confined in kinetically arrested, jammed clusters, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the mutants, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in the two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell-cell tension, and cellular motility. Using a cell shape-tension coupled bi-disperse vertex model, we reveal that interfacial tension at mutant-wild-type boundaries dictates whether mutants are eliminated, restrained, or expanded. Additionally, modulating the heterotypic interfacial tension alters mutant cluster fates. Together, our findings uncover a mechanical basis for tissue-specific oncogenesis by highlighting how interfacial mechanics between mutants and wild-type populations regulate tumor initiation and progression.

Keywords:  breast epithelial cells; cancer biology; lung epithelial cells; mammalian cells

DOI:  https://doi.org/10.7554/eLife.106893
Nature. 2026 Aug 05.

A tumour-derived organoid biobank maps cancer gene dependencies.

OCCAMS Consortium

Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR-Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR-RAS-MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.

DOI: https://doi.org/10.1038/s41586-026-10830-y
Curr Opin Genet Dev. 2026 Aug 05. pii: S0959-437X(26)00095-X. [Epub ahead of print]100 102528

What's in a niche? Elucidating the role of the ECM in cell fate commitment.

Atoosa Amel, Anna Alemany.

Emerging work is shedding light on how integrin engagement can be harnessed to modulate cell behaviour by deepening our understanding of the downstream signalling cascades activated upon extracellular matrix (ECM) binding. In many culture systems, integrin-mediated adhesion works in concert with exogenously supplied growth factors or small molecules to guide differentiation. Altogether, cell-ECM interactions via integrin-mediated adhesion are a driving force in regulating stem cell fate. In this mini-review, we highlight key studies that demonstrate how the ECM influences lineage specification in both in vivo and in vitro settings, and we discuss how these insights may shape the future of organoid culture systems.

DOI: https://doi.org/10.1016/j.gde.2026.102528
Nature. 2026 Aug 05.

A dependency map enhanced with next-generation 3D cancer models.

James V Neiswender, Samuel Maffa, Lisa Brenan, Dina ElHarouni, Yejie Yun, Isabella Boyle, Kirsty Wienand, Haider Inam, Tate Bertea, Ashley Anderson, Megan Wong, Matias Enriquez, Evan Lenz, Beatriz Villafranca, Nora Shanks, Mary Hager, Nia Lloyd, Hannah Shadmany, Sarah J Wie, Harry Liang, Konnor Yunghans, Xiaomeng Zhang, Lauren Golden, Hannah Harris, Serena Day, Philip Montgomery, Samantha Stokes, Ross M Giglio, Cynthia Hajal, James R Whittle, Guadalupe Garcia, Caitlin E Mills, Mehdi Touat, Kristine Pelton, Hongyu Li, Prem Sai Prabhakar, Sonja Herter, Zoe Hoffmann Kamrat, Dan Gui, Julien Dilly, Chen Khuan Wong, Jimmy A Guo, Sangita Pal, Yossef Baidi, Ryan Johnston, Daniel D Brown, Sonam Bhatia, Peter S Winter, Srivatsan Raghavan, Rameen Beroukhim, Eva Colas, David L Spector, Adam J Bass, Peter K Sorger, Yu Chen, Sarah J Hill, Steffi Oesterreich, Adrian V Lee, Himisha Beltran, Jesse S Boehm, Yuen-Yi Tseng, David E Root, William C Hahn, Andrew J Aguirre, Catarina D Campbell, Keith L Ligon, Joshua M Dempster, Tsukasa Shibue, Francisca Vazquez.

Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over 1,300 cell lines have led to the discovery of new therapeutic strategies across multiple tumour types2. However, mapping cancer vulnerabilities using traditional cell lines has limitations, including insufficient cancer subtype representation and the impact of culture conditions on perturbation responses. Here we perform 147 genome-scale CRISPR screens and multi-omic characterizations of next-generation (NextGen) cancer models (organoids and spheroids) across 10 cancer types. This strategy enables the expansion of DepMap to cover new genomic and molecular subtypes and to identify new biomarker-associated vulnerabilities. These new models also preserve transcriptional programs that are silenced in traditional cell lines and facilitate the discovery of specific gene dependencies associated with these programs. Comparisons of traditional and NextGen cancer models enable further identification of distinct effects of growth format and culture medium on gene essentiality. The integrated dataset combines data from both model types to offer a valuable, expansive resource for exploring cancer vulnerabilities and is accessible via the DepMap portal.

DOI: https://doi.org/10.1038/s41586-026-10843-7
Nature. 2026 Aug 05.

The Virtual Tissues foundation model resolves spatial proteomics across scales.

Johann Wenckstern, Eeshaan Jain, Benedikt von Querfurth, Yexiang Cheng, Kiril Vasilev, Matteo Pariset, Phil F Cheng, Petros Liakopoulos, Olivier Michielin, Andreas Wicki, Gabriele Gut, Charlotte Bunne.

Spatial proteomics technologies have transformed our understanding of complex tissue architecture in cancer but present unique challenges for computational analysis1. Each study uses a different marker panel and protocol, and most methods are tailored to single cohorts, which limits knowledge transfer and robust biomarker discovery. Here we present Virtual Tissues (VirTues), a general-purpose foundation model for spatial proteomics that learns marker-aware, multi-scale representations of proteins, cells, niches and tissues directly from multiplex imaging data. From a single pretrained backbone, VirTues supports marker reconstruction, cell segmentation and typing, niche annotation, spatial biomarker discovery and patient stratification, including zero-shot annotation across heterogeneous panels and datasets. In triple-negative breast cancer, VirTues-derived biomarkers predict anti-PD-L1 chemo-immunotherapy response2 and stratify disease-free survival in an independent cohort3, outperforming state-of-the-art biomarkers derived from the same datasets and current clinical stratification schemes.

DOI: https://doi.org/10.1038/s41586-026-10884-y
Mol Genet Genomics. 2026 Aug 07. pii: 165. [Epub ahead of print]301(1):

Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling.

Congxiu Huang, Wei Zhang, Xiaoyu Ma, Xuefeng Li, Xiaoge Sun.

  Cervical cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. Although genomic alterations in oncogenic signaling pathways have been implicated in cervical carcinogenesis, the functional impact of recurrent driver mutations remains incompletely understood. Whole-exome sequencing was performed on paired tumor and matched non-tumor tissues from 61 patients to identify recurrent somatic alterations. Functional significance was subsequently evaluated using cervical cancer cell models through proliferation, invasion, apoptosis, and signaling pathway analyses. Tumorigenic potential was further assessed using a xenograft mouse model. Genomic profiling identified PIK3CA as one of the most frequently mutated genes in cervical cancer. Functional analyses demonstrated that PIK3CA E545K mutation (PIK3CA-E545K-MUT) significantly enhanced tumor cell proliferation and invasive capacity while suppressing apoptosis. Mechanistically, these effects were associated with sustained activation of the AKT/mTOR signaling pathway, as evidenced by increased phosphorylation of key downstream effectors. Consistently, in vivo xenograft experiments confirmed that PIK3CA-E545K-MUT-driven signaling activation promoted tumor growth. Our findings establish a functional and mechanistic link between recurrent PIK3CA-E545K-MUT and aggressive tumor behavior in cervical cancer via AKT/mTOR pathway activation. These results provide experimental support for targeting the PI3K/AKT/mTOR axis as a potential therapeutic strategy in cervical cancer.

Keywords:   PIK3CA mutation; AKT/mTOR signaling pathway; Cervical cancer; Genomic sequencing; Tumor growth and invasion

DOI:  https://doi.org/10.1007/s00438-026-02495-z