Modeling human gastric cancers in immunocompetent mice DOI Creative Commons

Weihong Zhang,

Shilong Wang,

Hui Zhang

et al.

Cancer Biology and Medicine, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 18

Published: June 28, 2024

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. This determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions the stomach; displays high heterogeneity, with different cellular origins diverse histological molecular features. heterogeneity has hindered efforts to fully understand pathology GC develop efficient therapeutics. In past decade, great progress been made in study GC, particularly subtyping, investigation immune microenvironment, defining evolutionary path dynamics. Preclinical mouse models, immunocompetent models that mimic features human combination organoid culture clinical studies, have provided powerful tools for elucidating mechanisms underlying evasion, development novel therapeutic strategies. Herein, we first briefly introduce current challenges subsequently summarize emphasizing potential application genetically engineered antitumor immunity immunotherapy studies.

Language: Английский

Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis DOI
Michelle Leung, Charles Swanton, Nicholas McGranahan

et al.

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Language: Английский

Citations

1
Quantifying the adaptive landscape of commensal gut bacteria using high-resolution lineage tracking DOI Creative Commons
Daniel P.G.H. Wong, Benjamin H. Good

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 21, 2024

Gut microbiota can adapt to their host environment by rapidly acquiring new mutations. However, the dynamics of this process are difficult characterize in dominant gut species complex vivo environment. Here we show that fine-scale genome-wide transposon libraries enable quantitative inferences these evolutionary forces. By analyzing >400,000 lineages across four human Bacteroides strains gnotobiotic mice, observed positive selection on thousands cryptic variants - most which were unrelated original gene knockouts. The spectrum fitness benefits varied between species, and displayed diverse tradeoffs over time different dietary conditions, enabling underlying function. These results suggest within-host adaptations arise from an intense competition numerous contending variants, strongly influence emergent tradeoffs.

Language: Английский

Citations

8
Emerging strategies to investigate the biology of early cancer DOI
Ran Zhou, Xiwen Tang, Yuan Wang

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(12), P. 850 - 866

Published: Oct. 21, 2024

Language: Английский

Citations

7
Evolution of evolvability in rapidly adapting populations DOI

James T. Ferrare,

Benjamin H. Good

Nature Ecology & Evolution, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

Language: Английский

Citations

6
Recapitulating the adenoma–carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch-repair-deficient human colon organoids DOI Creative Commons
Tomohiro Mizutani, Matteo Boretto,

Sangho Lim

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Carcinogenesis results from the sequential acquisition of oncogenic mutations that convert normal cells into invasive, metastasizing cancer cells. Colorectal exemplifies this process through its well-described adenoma-carcinoma sequence, modeled previously using clustered regularly interspaced short palindromic repeats (CRISPR) to induce four consecutive in wild-type human gut organoids. Here, we demonstrate long-term culture mismatch-repair-deficient organoids allows selection spontaneous withdrawal Wnt agonists, epidermal growth factor (EGF) agonists and bone morphogenetic protein (BMP) antagonist Noggin, while TP53 were selected addition Nutlin-3. Thus, sequentially acquired AXIN1 AXIN2 (Wnt pathway), TP53, ACVR2A BMPR2 (BMP pathway) NRAS (EGF gaining complete independence stem cell niche factors. Quadruple-pathway (Wnt, EGF receptor, p53 BMP) mutant formed solid tumors upon xenotransplantation. This demonstrates carcinogenesis can be recapitulated a DNA repair-mutant background vitro targets pathways.

Language: Английский

Citations

4
Permission to pass: on the role of p53 as a gatekeeper for aneuploidy DOI Creative Commons
Joana F. Marques, Geert J.P.L. Kops

Chromosome Research, Journal Year: 2023, Volume and Issue: 31(4)

Published: Oct. 21, 2023

Aneuploidy-the karyotype state in which the number of chromosomes deviates from a multiple haploid chromosome set-is common cancer, where it is thought to facilitate tumor initiation and progression. However, poorly tolerated healthy cells: during development tissue homeostasis, aneuploid cells are efficiently cleared population. It still largely unknown how cancer become, adapt being, aneuploid. P53, gatekeeper genome, has been proposed guard against aneuploidy. Aneuploidy genomes strongly correlates with mutations TP53, p53 prevent propagation cells. Whether also participates preventing mistakes cell division that lead aneuploidy under debate. In this review, we summarize current understanding role protecting aneuploidy, explore consequences functional loss for cancer.

Language: Английский

Citations

11
Organoids from pluripotent stem cells and human tissues: When two cultures meet each other DOI Creative Commons
Benedetta Artegiani, Delilah Hendriks

Developmental Cell, Journal Year: 2025, Volume and Issue: 60(4), P. 493 - 511

Published: Feb. 1, 2025

Language: Английский

Citations

0
Deciphering precursor cell dynamics in esophageal preneoplasia via genetic barcoding and single-cell transcriptomics DOI Creative Commons

Jinho Jang,

Kyung-Pil Ko, Jie Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Cancer cells exhibit high heterogeneity and lineage plasticity, complicating studies of tumorigenesis development therapies. Recently, preneoplastic cells, although histologically normal, have been shown to possess plasticity early genetic alterations, yet their origins trajectories remain unclear. Herein, we introduce a lineage-tracing tool integrating barcoding with single-cell RNA sequencing map esophageal cell lineages. We identified precursor (PNPCs) as distinct progenitor-like population unique transcriptional profiles contributing proliferative basal populations. To enhance mapping, developed the eXamined Ridge (XR) score, accurately identifying high-plasticity cells. Nfib Qk emerged conserved PNPC markers, peaking in preneoplasia declining after malignant transformation. These findings reveal PNPCs key players highlight potential biomarkers for cancer detection therapeutic intervention, offering new strategies preventing progression.

Language: Английский

Citations

0
Biotechnological advances in 3D modeling of cancer initiation. Examples from pancreatic cancer research and beyond DOI Creative Commons

Charles Handschin,

Hala Shalhoub,

Aurélien Mazet

et al.

Biofabrication, Journal Year: 2025, Volume and Issue: 17(2), P. 022008 - 022008

Published: Feb. 28, 2025

In recent years, biofabrication technologies have garnered significant attention within the scientific community for their potential to create advancedin vitrocancer models. While these been predominantly applied model advanced stages of cancer, there exists a pressing need develop pertinent, reproducible, and sensitive 3D models that mimic cancer initiation lesions native tissue microenvironment. Such hold profound relevance comprehending intricacies initiation, devise novel strategies early intervention, and/or conduct sophisticated toxicology assessments putative carcinogens. Here, we will explain pivotal factors must be faithfully recapitulated when constructing models, with specific focus on pancreatic lesions. By synthesizing current state research in this field, provide insights into advances breakthroughs. Additionally, delineate key technological biological challenges necessitate resolution future endeavors, thereby paving way more accurate insightfulin

Language: Английский

Citations

0
RecurrentERBB2alterations are associated with esophageal adenocarcinoma brain metastases DOI Creative Commons

Nora Lawson,

Lingqun Ye, Chae Yun Cho

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Brain metastases in esophageal adenocarcinoma (EAC) patients are associated with poor prognosis and remain understudied. We performed multi-omics analysis whole-genome sequencing single-cell spatial transcriptomics on the brain matched primary tumors. Our identified ERBB2 as a recurrent oncogene EAC metastases, 9 out of 10 cases harboring amplifications. Single-cell multi-region revealed that alterations, occur early during disease progression monoclonal seeding. Although median survival our cohort was 13 months, one patient HER2 antibody-drug conjugate therapy remains long-term survivor beyond 34 months. Interestingly, sole without an alteration had JAK2 deletion, high T cell infiltration lesion, survived 35 months after immune checkpoint therapy. findings have significant clinical implications for treatment management metastases. is targetable EAC-BM High -deleted tumor links to immunotherapy response Genomic instability marked by presence micronuclei ecDNAEAC metastasis resembles seeding events.

Language: Английский

Citations

0