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Emerging strategies to investigate the biology of early cancer

Nature Reviews Cancer volume 24, pages 850–866 (2024)Cite this article

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Abstract

Early detection and intervention of cancer or precancerous lesions hold great promise to improve patient survival. However, the processes of cancer initiation and the normal–precancer–cancer progression within a non-cancerous tissue context remain poorly understood. This is, in part, due to the scarcity of early-stage clinical samples or suitable models to study early cancer. In this Review, we introduce clinical samples and model systems, such as autochthonous mice and organoid-derived or stem cell-derived models that allow longitudinal analysis of early cancer development. We also present the emerging techniques and computational tools that enhance our understanding of cancer initiation and early progression, including direct imaging, lineage tracing, single-cell and spatial multi-omics, and artificial intelligence models. Together, these models and techniques facilitate a more comprehensive understanding of the poorly characterized early malignant transformation cascade, holding great potential to unveil key drivers and early biomarkers for cancer development. Finally, we discuss how these new insights can potentially be translated into mechanism-based strategies for early cancer detection and prevention.

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Fig. 1: The multistage malignant transformation cascade of normal cells.
Fig. 2: Clinical samples and preclinical models for early cancer.

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Acknowledgements

Y.W. gratefully acknowledges funding from the National Natural Science Foundation of China (82425037, 92359303, 82273117), the National Key R&D Program of China, Stem Cell and Translational Research (2022YFA1105200), Sichuan Science and Technology Program (2023ZYD0128, 2024NSFSC0059) and West China Hospital (ZYYC23023). R.Z. thanks the National Natural Science Foundation of China (82303975), the China Postdoctoral Science Foundation (2022TQ0226 and 2023M742492) and West China Hospital (2023HXBH100). After completing the final manuscript, the authors utilized ChatGPT (OpenAI, https://chat.openai.com/) to proofread the final draft.

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  1. Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China

    Ran Zhou, Xiwen Tang & Yuan Wang

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  1. Ran Zhou
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  2. Xiwen Tang
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  3. Yuan Wang
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Contributions

R.Z. and X.T. researched data for the article. R.Z. and Y.W. wrote the article. All authors reviewed or edited the manuscript before submission.

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Correspondence to Yuan Wang.

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Related links

ATCC: https://www.atcc.org

inferCNV: https://github.com/broadinstitute/infercnv

PreCancer Atlas: https://prevention.cancer.gov/major-programs/pre-cancer-atlas-pca

siCNV: https://github.com/aerickso/SpatialInferCNV

Glossary

Acinar-to-ductal metaplasia

The transformation of pancreatic acinar cells into duct-like cells in response to pancreatic injury or chronic stress that is considered a precursor to pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

Actinic keratosis

A rough, dry and scaly patch or plaque on the skin, considered a precursor to squamous cell carcinoma of the skin, that is associated with risk factors such as sun exposure, human papillomavirus, fair skin, immunosuppressive therapy and age.

Adenomas

Benign tumours originating from glandular epithelial tissue in various organs, including the colon, pituitary gland, thyroid, adrenal glands and liver.

Assay for transposase-accessible chromatin with sequencing

(ATAC-seq). A widely utilized method to assess the accessibility of chromatin within cells.

Assembloids

3D in vitro tissue models that integrates multiple organoid types or cell lineages to replicate the complex interactions and architecture of tissues.

Atypical adenomatous hyperplasia

A term predominantly used in lung pathology to describe precursor lesions of lung adenocarcinoma; however, it can occasionally be applied to other organs to denote abnormal, precancerous growth patterns in glandular tissues.

Atypical endometrial hyperplasia

Also known as endometrial intraepithelial neoplasia. A precancerous condition characterized by the abnormal proliferation of the cells lining the endometrium with atypical cellular features.

Autochthonous mouse models

Mouse models in which cancer arises naturally within the mouse, typically induced through genetic modifications or exposure to carcinogens.

Barrett’s oesophagus

Barrett’s oesophagus precedes the onset of oesophageal adenocarcinoma and involves a metaplastic change in the mucosal cells within the lower part of the oesophagus, a response to damage from gastro-oesophageal reflux.

Chronic atrophic gastritis

A long-term condition characterized by the chronic inflammation of the stomach lining, leading to the gradual loss of gastric glandular cells, resulting in stomach lining atrophy that can be accompanied by changes in the structure of the stomach lining, potentially leading to intestinal metaplasia and an increased risk of gastric cancer.

Club cells

A type of non-ciliated epithelial cells located in the bronchioles of the lungs, which is essential for maintaining the health and function of the respiratory epithelium.

Dysplasia

An abnormal growth or development of cells within a tissue, exhibiting irregularities in size, shape, organization and cellular structure, with severity ranging from mild to severe, with high-grade dysplasia carrying a risk of progressing to cancer.

Extrachromosomal DNA

(ecDNA). Any DNA that is often larger than 1 Mb and is located outside the chromosomes.

Familial adenomatous polyposis

A type of syndromic polyp associated with genetic syndromes that predisposes individuals to the development of hundreds to thousands of adenomatous polyps in the colon and rectum, which almost inevitably progresses to colorectal cancer.

Field cancerization

A process through which a broad region of cells within a tissue or organ undergoes genetic and epigenetic alterations, thereby predisposing the entire field to an elevated risk of developing cancer.

Hyperplasia

Hyperplasia is a reversible process that involves an increase in the number of cells in a tissue, which can occur owing to physiological or pathological triggers.

Intravital microscopy

(IVM). A technique to visualize cells within a living organism using fluorescent markers or dyes that encompasses various methods, including confocal microscopy, two-photon microscopy and multiphoton microscopy.

Large language models

Advanced machine learning algorithms designed to grasp the intricacies, patterns and subtleties of human language by analysing data sets containing billions of words.

Leukoplakia

White patches or plaques in the oral or genital regions with the potential to progress to squamous cell carcinoma, which is associated with risk factors including tobacco use, alcohol consumption, chronic irritation, viral infections such as HPV, and age and gender.

Low-grade intraepithelial neoplasia

(LGIN). A precancerous condition characterized by the presence of mildly abnormal epithelial cells confined to the epithelial layer of the oesophagus that has a lower risk of progression to oesophageal cancer than high-grade intraepithelial neoplasia (HGIN).

Metaplasia

A reversible process through which one differentiated cell is replaced by another cell type, typically in response to persistent irritation or inflammation.

Monoclonal gammopathy of undetermined significance

A precancerous condition with a modest risk of progression to more severe plasma cell disorders that is characterized by the presence of an abnormal monoclonal protein in the blood, produced by a clone of plasma cells.

Neoplastic polyps

Polyps with the potential to develop into colorectal cancer that can be classified into adenomatous polyps (including tubular, tubulovillous and villous types) and serrated polyps (including sessile serrated lesions and traditional serrated adenomas).

Pancreatic intraepithelial neoplasia

(PanIN). These precursor lesions to pancreatic ductal adenocarcinoma that encompass a spectrum of dysplastic changes are microscopic abnormalities found in the epithelial cells lining the pancreatic ducts and are not detectable through standard imaging techniques.

Precancerous cells

Cancer precursor cells that harbour common cancer driver mutations but exist in tissues without clinical evidence of precursor lesions.

Precancerous lesions

Morphological changes in tissues resulting from the acquisition of driver events in individual cells that undergo positive selection and clonal expansion within normal tissues, leading to tissue remodelling.

Pulmonary nodules

Small, abnormal areas that appear in the lung tissue that can result from infections or scarring, which could potentially lead to lung cancer.

Single-cell multi-omics

An advanced genomic technique that enables the simultaneous analysis of multiple types of biological signals such as the genome, transcriptome, proteome and metabolome within the same cell.

Smouldering multiple myeloma

An asymptomatic, precancerous condition that is considered an intermediate stage between monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma and is characterized by elevated levels of monoclonal protein and a higher percentage of abnormal plasma cells in the bone marrow.

Spatial transcriptomics

A method that enables the spatial visualization and quantification of gene expression within a tissue.

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Zhou, R., Tang, X. & Wang, Y. Emerging strategies to investigate the biology of early cancer. Nat Rev Cancer 24, 850–866 (2024). https://doi.org/10.1038/s41568-024-00754-y

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