What if we could identify cells that will become cancerous before they transform into a tumor? In a recent paper in Nature Cancer, Yao et al. designed bioluminescent/fluorescent reporter proteins for the commonly mutated p53 protein to trace precancerous cells in noncancerous tissues. Their technical advance sheds light on the earliest stages of cancer cell development, and will hopefully inform strategies for developing better early cancer detection tools.
Towards a Better Understanding of Early Tumorigenesis
How does cancer begin? This question has puzzled researchers for decades and has been tackled with dozens of tools, including sophisticated genomic profiling. While many mysteries remain, one of the common features of tumorigenesis is the accumulation of multiple mutations over time. It is not a single event that turns a harmless cell into a cancerous one.
So, it follows that for early detection of cancer, normal cells harboring common cancer driver mutations are the most likely to be precancerous – right? Actually, a surprising number of cells in aged, noncancerous tissues have these mutations and even clonally expand, but never go on to be cancerous. Being able to accurately identify which cells are precancerous is crucial for understanding tumorigenesis and developing methods for early cancer detection and prevention.
Creating Protein-Level Mutant p53 Reporters
One of the most commonly mutated tumor suppressors is p53, which is mutated in approximately 50% of all cancers. In a recent paper in Nature Cancer, Yao et al. leveraged a cancer-specific stabilization event of mutant p53 to develop a reporter that could trace precancerous cell clones in noncancerous tissues.
Previous studies identified that mutated p53 proteins undergo a stabilization event in precancerous human samples and mouse models that does not occur in cells with wild-type p53 or noncancerous mutated p53 cells. However, it is unknown whether these stabilized cells directly give rise to tumors or not.
In order to trace the dynamics of these mutant p53 cells, Yao et al. used CRISPR-Cas9 to generate two bioluminescent/fluorescent mutant p53 reporter proteins. From the luminescent readout of foci of increasing intensity (i.e. concentration of mutant p53) at sites in various mouse models of cancer, these reporters accurately identified cells in the mice that subsequently developed into cancer, prior to any symptoms or other indicators.
In a model of thymic lymphoma, the authors identified that an amino acid-uptake pathway was highly upregulated in these precancerous cells, and that blocking it with a drug suppressed tumorigenesis at this early stage, but not in later stage cancers. Further monitoring of the mutant p53 cells after treatment revealed potential drug resistance mechanisms and opens up another potential application for these reporters.
The Importance of Early Cancer Detection
What’s remarkable about this paper is that the design of the reporters allows the precancerous cells to be identified and monitored non-invasively, using live imaging to visualize the luminescent readouts. The precancerous cells identified through their stabilized mutant p53 proteins were captured 4-6 weeks before their growth into end-stage tumors, even when the tissues looked completely normal, the cells were at a relatively low concentration, and their gene expression patterns were still significantly different from advanced cancers.
These findings are likely part of the explanation for why cancers caught at earlier stages are often much easier to treat. Not only is the total number of cells smaller (with metastasis less likely), but the cancer cells have fewer mutations that could lend them resistance to treatment. The focus of cancer research has shifted to include both cancer treatment and early cancer detection and prevention. This is a major technical advance in the ability of researchers to identify precancerous cells in noncancerous tissues, improving our understanding of the early molecular events in cancer.
Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help
The authors relied heavily on single-cell RNA-seq data analysis to compare the genomic profiles of cancerous and precancerous cells, shedding light on the distinct molecular events at the beginning of tumorigenesis and potential mechanisms of cancer drug resistance. The generation, storage and analysis of biological data like scRNA-seq data is faster and more accessible than ever before. From pipeline development and software engineering to deploying existing bioinformatics tools, Bridge Informatics can help you on every step of your research journey.
As experts across data types from leading sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing and interpreting genomic and transcriptomic data. Bridge Informatics’ bioinformaticians are trained bench biologists, so they understand the biological questions driving your computational analysis. Click here to schedule a free introductory call with a member of our team.
Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].