bims-gerecp 2025-03-09 papers

bims-gerecp

Biomed News

on Gene regulatory networks of epithelial cell plasticity

Issue of 2025–03–09
ten papers selected by
Xiao Qin, University of Oxford

Gene regulatory network inference during cell fate decisions by perturbation strategies.
Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer.
The landscape of cell lineage tracing.
Evolutionary fingerprints of epithelial-to-mesenchymal transition.
Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer.
Exposomal determinants of non-genetic plasticity in tumor initiation.
A Multimodal Framework to Uncover Drug-Responsive Subpopulations in Triple-Negative Breast Cancer.
Cost-effectiveness analysis of sequential two-step screening versus direct colonoscopy screening for colorectal cancer: a large-scale survey in Eastern China.
Revisiting the Starting Age of Colorectal Cancer Screening for Average-Risk Asian Population: a cost-effectiveness analysis.
Clonal memory of colitis accumulates and promotes tumor growth.

NPJ Syst Biol Appl. 2025 Mar 04. 11(1): 23

Gene regulatory network inference during cell fate decisions by perturbation strategies.

Qing Hu, Xiaoqi Lu, Zhuozhen Xue, Ruiqi Wang.

With rapid advances in biological technology and computational approaches, inferring specific gene regulatory networks from data alone during cell fate decisions, including determining direct regulations and their intensities between biomolecules, remains one of the most significant challenges. In this study, we propose a general computational approach based on systematic perturbation, statistical, and differential analyses to infer network topologies and identify network differences during cell fate decisions. For each cell fate state, we first theoretically show how to calculate local response matrices based on perturbation data under systematic perturbation analysis, and we also derive the wild-type (WT) local response matrix for specific ordinary differential equations. To make the inferred network more accurate and eliminate the impact of perturbation degrees, the confidence interval (CI) of local response matrices under multiple perturbations is applied, and the redefined local response matrix is proposed in statistical analysis to determine network topologies across all cell fates. Then in differential analysis, we introduce the concept of relative local response matrix, which enables us to identify critical regulations governing each cell state and dominant cell states associated with specific regulations. The epithelial to mesenchymal transition (EMT) network is chosen as an illustrative example to verify the feasibility of the approach. Largely consistent with experimental observations, the differences of inferred networks at the three cell states can be quantitatively identified. The approach presented here can be also applied to infer other regulatory networks related to cell fate decisions.

DOI: https://doi.org/10.1038/s41540-025-00504-2
bioRxiv. 2025 Feb 22. pii: 2025.02.17.638725. [Epub ahead of print]

Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer.

Ahmed Mahmoud, Philip H Choi, Christine Sukhwa, Jura Pintar, Henry Walch, Nan Zhao, Jonathan Bermeo, Sebastian Chung, Manisha Raghavan, Samhita Bapat, Qingwen Jiang, Georgios Karagkounis, Julia Meredith, Michael Giarrizzo, Canan Firat, Andrea Cercek, Michael B Foote, Nikolaus Schultz, Walid K Chatila, Garrett M Nash, Jinru Shia, Francisco Sanchez-Vega, Steven Larson, Arvin C Dar, Neal Rosen, Karuna Ganesh.

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRAS MULTI -ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.

DOI: https://doi.org/10.1101/2025.02.17.638725
Sci China Life Sci. 2025 Feb 28.

The landscape of cell lineage tracing.

Ye Feng, Guang Liu, Haiqing Li, Lin Cheng.

  Cell fate changes play a crucial role in the processes of natural development, disease progression, and the efficacy of therapeutic interventions. The definition of the various types of cell fate changes, including cell expansion, differentiation, transdifferentiation, dedifferentiation, reprogramming, and state transitions, represents a complex and evolving field of research known as cell lineage tracing. This review will systematically introduce the research history and progress in this field, which can be broadly divided into two parts: prospective tracing and retrospective tracing. The initial section encompasses an array of methodologies pertaining to isotope labeling, transient fluorescent tracers, non-fluorescent transient tracers, non-fluorescent genetic markers, fluorescent protein, genetic marker delivery, genetic recombination, exogenous DNA barcodes, CRISPR-Cas9 mediated DNA barcodes, and base editor-mediated DNA barcodes. The second part of the review covers genetic mosaicism, genomic DNA alteration, TCR/BCR, DNA methylation, and mitochondrial DNA mutation. In the final section, we will address the principal challenges and prospective avenues of enquiry in the field of cell lineage tracing, with a particular focus on the sequencing techniques and mathematical models pertinent to single-cell genetic lineage tracing, and the value of pursuing a more comprehensive investigation at both the spatial and temporal levels in the study of cell lineage tracing.

Keywords:  cell lineage; prospective tracing; retrospective tracing

DOI:  https://doi.org/10.1007/s11427-024-2751-6
Nature. 2025 Mar 05.

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Luigi Perelli, Li Zhang, Sarah Mangiameli, Francesca Giannese, Krishnan K Mahadevan, Fuduan Peng, Francesca Citron, Hania Khan, Courtney Le, Enrico Gurreri, Federica Carbone, Andrew J C Russell, Melinda Soeung, Truong Nguyen Anh Lam, Sebastian Lundgren, Sujay Marisetty, Cihui Zhu, Desiree Catania, Alaa M T Mohamed, Ningping Feng, Jithesh Jose Augustine, Alessandro Sgambato, Giampaolo Tortora, Giulio F Draetta, Giovanni Tonon, Andrew Futreal, Virginia Giuliani, Alessandro Carugo, Andrea Viale, Michael P Kim, Timothy P Heffernan, Linghua Wang, Raghu Kalluri, Davide Cittaro, Fei Chen, Giannicola Genovese.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

DOI: https://doi.org/10.1038/s41586-025-08671-2
Cancer Discov. 2025 Mar 04.

Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer.

Can Chen, Yimin Cai, Wenlong Hu, Kai Tan, Zequn Lu, Xuanyu Zhu, Ziying Liu, Chunyi He, Guangping Xu, Ruizhe Zhang, Caibo Ning, Shuheng Ruan, Jiayan Gao, Xiaojun Yang, Yongchang Wei, Xu Zhu, Xiangpan Li, Faxi Wang, Fubing Wang, Jiaoyuan Li, Meng Jin, Bin Li, Ying Zhu, Jianbo Tian, Xiaoping Miao.

Colorectal cancer (CRC) is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. Here, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular crosstalk during CRC development. Additionally, we created a CRC sc-eQTL map identifying 16,833 significant pairs across 28 cell subtypes, with over 76% of sc-eQTLs being cell-type-specific and fewer than 15% detectable in bulk datasets. A polygenic risk score (PRS) derived from sc-eQTLs substantially improved CRC risk prediction. We prioritized rs4794979 that is associated with an increased CRC risk (OR=1.11, P=2.04×10-12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts (CAFs), simultaneously induces CD8+ T cells exhaustion via LGALS9-TIM3 axis, thereby facilitating CRC development. Blocking LGALS9-TIM3 axis enhanced anti-PD-1 therapy to inhibit CRC progression.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1561
Trends Cancer. 2025 Feb 28. pii: S2405-8033(25)00011-1. [Epub ahead of print]

Exposomal determinants of non-genetic plasticity in tumor initiation.

Davide Carra, Silvana C E Maas, Jose A Seoane, Direna Alonso-Curbelo.

  The classical view of cancer as a genetically driven disease has been challenged by recent findings of oncogenic mutations in phenotypically healthy tissues, refocusing attention on non-genetic mechanisms of tumor initiation. In this context, gene-environment interactions take the stage, with recent studies showing how they unleash and redirect cellular and tissue plasticity towards protumorigenic states in response to the exposome, the ensemble of environmental factors impinging on tissue homeostasis. We conceptualize tumor-initiating plasticity as a phenotype-transforming force acting at three levels: cell-intrinsic, focusing on mutant epithelial cells' responses to environmental variation; reprogramming of non-neoplastic cells of the host, leading to protumor micro- and macroenvironments; and microbiome ecosystem dynamics. This perspective highlights cell, tissue, and organismal plasticity mechanisms underlying tumor initiation that are shaped by the exposome, and how their functional investigation may provide new opportunities to prevent, detect, and intercept cancer-promoting plasticity.

Keywords:  cellular plasticity; exposome; inflammation; macroenvironment; microenvironment; tumor initiation

DOI:  https://doi.org/10.1016/j.trecan.2025.01.010
bioRxiv. 2025 Feb 19. pii: 2025.02.14.638274. [Epub ahead of print]

A Multimodal Framework to Uncover Drug-Responsive Subpopulations in Triple-Negative Breast Cancer.

Yue Wang, Santiago Haase, Austin Whitman, Adriana Beltran, Philip M Spanheimer, Elizabeth Brunk.

Understanding how individual cancer cells adapt to drug treatment is a fundamental challenge limiting precision medicine cancer therapy strategies. While single-cell technologies have advanced our understanding of cellular heterogeneity, efforts to connect the behavior of individual cells to broader tumor drug responses and uncover global trends across diverse systems remain limited. There is a growing availability of single-cell and bulk omics data, but a lack of centralized tools and repositories makes it difficult to study drug response globally, especially at the level of single-cell adaptation. To address this, we present a multimodal framework that integrates bulk and single-cell treated and untreated transcriptomics data to identify drug responsive cell populations in triple-negative breast cancer (TNBC). Our framework leverages population-scale bulk transcriptomics data from TNBC samples to define seven main "identities", each representing unique combinations of biologically relevant genes. These identities are dynamic and trackable, allowing us to map them onto single cells and uncover global patterns of how cell populations respond to drug treatment. Unlike static classifications, this approach captures the evolving nature of cellular states, revealing that a select few identities dominate and drive population-level responses during treatment. Crucially, our ability to decode these trends through the inherent noise of single-cell data provides a clearer picture of how heterogeneous cell populations adapt to therapy. By identifying the dominant identities and their dynamics, we can better predict how entire tumors respond to treatment. This insight is essential for designing precise combination therapies tailored to the unique heterogeneity of patient tumors, addressing the single-cell variations that ultimately determine therapeutic outcomes.

DOI: https://doi.org/10.1101/2025.02.14.638274
Front Oncol. 2025 ;15 1524172

Cost-effectiveness analysis of sequential two-step screening versus direct colonoscopy screening for colorectal cancer: a large-scale survey in Eastern China.

Yun Fu, Hao Li, Ao Xu, Zhongrong Yang, Peng Zhang, Weibing Wang.

   Objectives: Despite the implementation of colorectal cancer (CRC) screening programs in many regions worldwide over the past few decades, the cost-effectiveness of these programs has been questioned owing to their acceptance rates. In this study, we evaluated the cost-effectiveness of screening strategies, quantified the impact of colonoscopy acceptance rates, and analyzed the underlying factors driving individual preferences.
Methods: The cost-effectiveness of three strategies-no screening, sequential two-step screening (fecal immunochemical test and risk assessment, followed by colonoscopy), and colonoscopy screening-was evaluated from a societal perspective. This assessment was conducted using a decision-tree Markov model with the incremental cost-effectiveness ratio as the primary evaluation criterion.
Results: Sequential screening was more cost-effective than colonoscopy screening (19,335 vs. 27,379 United States dollars per quality-adjusted life year). Ideal sequential screening could prevent 32.2%(691/2147) CRC deaths, whereas colonoscopy screening at the same colonoscopy acceptance rate (20.3%) could prevent 17.6%(377/2147) CRC deaths. When the acceptance rate of direct colonoscopy surpasses the threshold of 37.2%, the resulting health benefits likely outweigh those achieved using a the sequential two-step screening approach.
Conclusions: Sequential screening is recommended for individuals in areas with constrained screening resources or during the early stages of regional screening program implementation. However, once screening habits are established, transitioning to direct colonoscopy screening becomes more favorable. Notably, reducing colonoscopy costs is the principal factor for enhancing an individual's willingness to undergo the procedure.

Keywords:  analysis; colorectal cancer; cost-effectiveness; screening; survey

DOI:  https://doi.org/10.3389/fonc.2025.1524172
Gastrointest Endosc. 2025 Feb 28. pii: S0016-5107(25)00141-5. [Epub ahead of print]

Revisiting the Starting Age of Colorectal Cancer Screening for Average-Risk Asian Population: a cost-effectiveness analysis.

Junjie Huang, Victor C W Chan, Mingtao Chen, Jamie Jie Mei Liew, Xianjing Liu, Chaoying Zhong, Jianli Lin, Junjie Hang, Claire Chenwen Zhong, Jinqiu Yuan, Wanghong Xu, Mellissa Withers, Andrew T Chan, Martin Cs Wong.

   BACKGROUND AND AIMS: One of the most prevalent and fatal tumors, colorectal cancer (CRC) has a significant impact on the use of healthcare services. Although Hong Kong's CRC screening program has been successful, it does not prioritize preventing early-onset colorectal cancer in people under 50. This study aimed to assess the cost-effectiveness of different starting ages for colorectal cancer (CRC) screening among an Asian population.
METHODS: We conducted a simulation study involving 100,000 individuals in Hong Kong who were screened using either fecal immunochemical test (FIT) or colonoscopy as primary screening methods at ages 40, 45, and 50 until age 75. The performance of different strategies was evaluated based on life-years gained, and cost-effectiveness was measured using the incremental cost-effectiveness ratio (ICER).
RESULTS: The ICERs for initiating FIT screening at age 50, screening starting at age 45, and screening starting at age 40 were USD 53,262, USD 67,892, and USD 86,554, respectively. For colonoscopy, the ICERs for initiating screening at ages 50,45 and 40 were USD 267,669, USD 312,848, and USD 372,090, respectively, respectively. Overall, the FIT strategy was found to be less costly. At 70%, 80% and 90% compliance rates, FIT at age 45 gained 2,135, 2,296 and 2,438 life years respectively; colonoscopy at age 45 gained 2,725, 2,798 and 2,855 life-years respectively. With increased compliance rates, FIT could save a similar number of life years as colonoscopy with lower cost.
CONCLUSIONS: Initiating CRC screening at age 45 using FIT in Hong Kong was determined to be a well-balanced and cost-effective strategy. This approach demonstrated a cost advantage over starting screening at age 40 and resulted in more lives saved compared to screening at age 50.

Keywords:  Starting age; colorectal cancer; cost-effectiveness; screening

DOI:  https://doi.org/10.1016/j.gie.2025.02.039
bioRxiv. 2025 Feb 17. pii: 2025.02.13.638099. [Epub ahead of print]

Clonal memory of colitis accumulates and promotes tumor growth.

Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang, Ena Oreskovic, Yan Hu, Daniel Zeve, Karina Sharma, Roni R Hyman, Qiming Zhang, Andrew Castillo, David T Breault, Ömer H Yilmaz, Jason D Buenrostro.

Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution, characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high resolution tracking of epigenomic memory. This reveals that inflammatory memory is propagated cell-intrinsically and inherited through stem cell lineages, with certain clones demonstrating dramatically stronger memory than others. Finally, we show that colitis primes stem cells for amplified expression of regenerative gene programs following oncogenic mutation that accelerate tumor growth. This includes a subpopulation of tumors that have exceptionally high AP-1 activity and the additional upregulation of pro-oncogenic programs. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.

DOI: https://doi.org/10.1101/2025.02.13.638099