bims-gerecp 2025-08-17 papers

Issue of 2025–08–17
five papers selected by
Xiao Qin, University of Oxford

bioRxiv. 2025 Jul 18. pii: 2025.07.15.664829. [Epub ahead of print]

Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early-Onset Colorectal Cancer.

Nicole C Huning, Munir H Buhaya, Victor V Nguyen, Afeefah Khazi-Syed, Haider A Ali, Adil Khan, Angela Fan, Robert C Fisher, Zhikai Chi, Indu Raman, Guangchun Chen, Chengsong Zhu, Mengxi Yu, Andrew R Jamieson, Sara Roccabianca, Victor D Varner, Cheryl M Lewis, Emina H Huang, Jacopo Ferruzzi.

The incidence of sporadic early onset colorectal cancer (EO CRC, under 50 years of age) is rising rapidly, yet the causes behind such rise remain poorly understood. Epidemiological studies indicate that lifestyle and environmental exposures may result in chronic inflammation, which is known to trigger tissue fibrosis. We hypothesized that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent hallmarks and drivers of EO CRC. Using primary human tissues, we show that EO CRC is associated with changes in collagen microstructure, increased stiffness and elevated viscosity of primary tumors. Spatial profiling and immunostaining reveal pro-fibrotic transcriptional programs in stromal cells, alongside enhanced mechanotransduction and proliferation in epithelial cells. In vitro, increased matrix stiffness promotes increased proliferation of epithelial cells in 2D and 3D colorectal cancer models. Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation.

DOI: https://doi.org/10.1101/2025.07.15.664829

Nat Rev Genet. 2025 Aug 15.

Tracing the evolution of sequencing into the era of genomic medicine.

Elaine R Mardis, Richard K Wilson.

Accelerated discovery in biomedical science is typically punctuated by technological advances, and the past decade has been exemplary regarding breakthroughs in our genomic understanding of human biology in health and disease. This phenomenon was facilitated by the availability of a human genome reference sequence and the development and continuous improvement of next-generation and single-molecule sequencing technologies, accompanied by advances in computational analytics. These fundamental tools have driven the emergence of innovative methods that capture different aspects of human cell biology, with exquisite detail genome wide, in a sequence-based readout. The resulting expansion of knowledge has poised these approaches for clinical adoption, fulfilling the original intention of decoding the human genome and ushering in the era of genomic medicine.

DOI: https://doi.org/10.1038/s41576-025-00884-5

Int J Mol Sci. 2025 Jul 23. pii: 7077. [Epub ahead of print]26(15):

Multiomics Signature Reveals Network Regulatory Mechanisms in a CRC Continuum.

Juan Carlos Higareda-Almaraz, Francesco Mattia Mancuso, Pol Canal-Noguer, Kristi Kruusmaa, Arianna Bertossi.

Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts.

Keywords: advanced adenomas; colorectal cancer; early detection; high-grade dysplasia; low-grade dysplasia; methylation; multiomics; regulatory network

DOI: https://doi.org/10.3390/ijms26157077

Nature. 2025 Aug 13.

Expanding the cytokine receptor alphabet reprograms T cells into diverse states.

Yang Zhao, Masato Ogishi, Aastha Pal, Leon L Su, Pingdong Tao, Hua Jiang, Grayson E Rodriguez, Xiaojing Chen, Qinli Sun, Lea Wenting Rysavy, Sam Limsuwannarot, Deepa Waghray, Anusha Kalbasi, K Christopher Garcia.

T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK-STAT signalling and gene expression programs1. However, the potential combinatorial diversity of JAK-STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γc) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK-STAT receptor pairings using an orthogonal cytokine receptor platform2-4 to expand the γc signalling code. We tested receptors from γc cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γc or are not naturally expressed on T cells. These receptors simulated their natural counterparts but also induced contextually unique transcriptional programs. This led to distinct T cell fates in tumours, including myeloid-like T cells with phagocytic capacity driven by orthogonal GSCFR (oGCSFR), and type 2 cytotoxic T (TC2) and helper T (TH2) cell differentiation driven by orthogonal IL-4R (o4R). T cells with orthogonal IL-22R (o22R) and oGCSFR, neither of which are natively expressed on T cells, exhibited stem-like and exhaustion-resistant transcriptional and chromatin landscapes, enhancing anti-tumour properties. Non-native receptor pairings and their resultant JAK-STAT signals open a path to diversifying T cell states beyond those induced by natural cytokines.

DOI: https://doi.org/10.1038/s41586-025-09393-1

Nat Rev Cancer. 2025 Aug 14.

Ageing, immune fitness and cancer.

Melissa Dolan, Kendra A Libby, Alison E Ringel, Peter van Galen, Sandra S McAllister.

The immune system undergoes substantial changes throughout life, with ageing broadly impacting immune cell composition, function and regenerative capacity. Emerging evidence suggests that age-associated changes in immune fitness - the ability to respond to and eliminate infection, pathogens and malignancy while maintaining self-tolerance - reshape antitumour immunity and influence the efficacy of immunotherapies. Technological advances in high-dimensional immunoprofiling have begun to reveal the complex interplay between ageing, immune fitness and cancer biology, uncovering new therapeutic vulnerabilities and challenges. In this Review, we discuss recent insights derived from age-resolved immunoprofiling of the human tumour microenvironment, how ageing haematopoiesis affects immune cells that contribute to the microenvironment and impact cancer progression, and what is known from preclinical modelling about the functional consequences of immune ageing on tumour control. We further highlight emerging age-stratified analyses of treatment responses, which are beginning to inform hypotheses about how ageing shapes immunotherapy outcomes. Together, these perspectives provide a framework for integrating age as a critical biological variable, underscore the need to consider age in both preclinical models and clinical trial design, and identify key challenges and priorities for the field moving forward.

DOI: https://doi.org/10.1038/s41568-025-00858-z