Mutant clones in normal epithelium outcompete and eliminate emerging tumours

Colom, Bartomeu; Herms, Albert; Hall, Michael W.; Dentro, Stefan C.; King, Charlotte; Sood, Roshan; Alcolea, Maria P.; Piedrafita, Gabriel; Fernández‐Antorán, David; Ong, Swee Hoe; Fowler, Joanna C.; Mahbubani, Krishnaa; Saeb‐Parsy, Kourosh; Gerstung, Moritz; Hall, Benjamin A.; Jones, Philip H.

doi:10.1038/s41586-021-03965-7

Cited by 113 publications

(91 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recent evidence has shown that most new tumors formed in the esophagus would naturally be eliminated due to the weaker viabilities of these newly formed tumors that of adjacent mutant epithelial cells, rather than differences in survival due to the involvement of the immune system [ 10 ]. Mutations are the potential origin of cancers.…”

Section: Immune Checkpoints In Cancer Therapymentioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

View full text Add to dashboard Cite

Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.

show abstract

Section: Immune Checkpoints In Cancer Therapymentioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

View full text Add to dashboard Cite

show abstract

“…7h,i ), consistent with observation of a higher proportion of centrosome amplification in these tumors. This contrasts with DEN induced tumors from p53 wt/wt mice, only 3% (2 of 64 tumors) exhibit CNA 27 .…”

Section: Resultsmentioning

confidence: 62%

“…In addition, within tumors, mutant Notch1 and Atp2a2 were positively selected ( Extended Data Fig. 7g ) 27 . We also looked for evidence of CNA in p53 */wt tumors using off target reads of the above sequencing.…”

Section: Resultsmentioning

confidence: 99%

p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition

Murai

Dentro

Ong

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Aging normal human epithelia, such as the esophagus, accumulate a substantial burden of TP53 mutant clones. These are the origin of most esophageal squamous carcinomas, in which biallelic TP53 disruption is almost frequent. However, the cellular mechanisms by which p53 mutants colonize the esophagus and participate in the subsequent stages of transformation are unclear. Here we show that inducing the p53R245W mutant in single esophageal progenitor cells in transgenic mice confers a proliferative advantage that drives clonal expansion but does not disrupt normal epithelial structure or function. Loss of the remaining p53 allele in mutant cells does not increase their competitive fitness, creating a bottleneck to the development of chromosomally unstable p53R245W/null epithelium. In carcinogenesis, p53 mutation does not initiate tumor formation, but tumors developing from areas with p53 mutation and LOH are larger and show extensive chromosomal instability compared to lesions arising in wild type epithelium. We conclude that p53 has distinct functions at different stages of carcinogenesis and that LOH within p53 mutant clones in normal epithelium is a critical step in malignant transformation.

show abstract

“…These results suggest that some genes favour the initial clonal expansion in normal tissues without the risk of further evolution into cancer 17 . Furthermore, clones with different carcinogenic potential might compete for space, especially within aging tissues 18,19 . These new carcinogenic insights also have major translational relevance.…”

Section: Introductionmentioning

confidence: 99%

A clinically annotated post-mortem approach to study multi-organ somatic mutational clonality in histologically healthy tissues

Luijts

Elliott

Siaw

et al. 2022

Preprint

View full text Add to dashboard Cite

Recent research on histologically healthy human tissues identified omnipresent mutational microclones, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1). These new insights are fundamentally changing current tumour evolution models, with broad oncological implications. Most studies are based on surgical remnant tissues, which are not available for many organs and rarely in a pan-organ setting (multiple organs from the same individual). Here, we describe an approach based on clinically annotated post-mortem tissues, derived from whole-body donors that are routinely used for educational purposes at human anatomy units. We validated this post-mortem approach using UV-exposed and unexposed epidermal skin tissues and confirm the presence of positively selected NOTCH1/2-, TP53- and FAT1-driven clones. No selection signals were detected in a set of immune genes or housekeeping genes. Additionally, we provide the first evidence for smoking-induced clonal changes in oral epithelia, likely underlying the origin of head and neck carcinogenesis. In conclusion, the whole-body donor-based approach provides a nearly unlimited healthy tissue resource to study mutational clonality and gain fundamental mutagenic insights in the presumed earliest stages of tumour evolution.

show abstract

Mutant clones in normal epithelium outcompete and eliminate emerging tumours

Cited by 113 publications

References 48 publications

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition

A clinically annotated post-mortem approach to study multi-organ somatic mutational clonality in histologically healthy tissues

Contact Info

Product

Resources

About