Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma DOI Creative Commons
Cecilia Roux, Siân Hamer, Abigail Shea

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 8, 2023

Abstract In paediatric cancers like neuroblastoma, limited genetic diversity emphasizes the role of phenotypic heterogeneity in driving malignancy. We investigated this phenomenon using experimental evolution and single-cell techniques neuroblastoma preclinical models. Our findings reveal that cells navigate multistable landscapes, named plasticity systems. These finely regulate their topology dynamics enabling tolerance, persistence, regrowth response to treatment. While preferential killing adrenergic (ADRN), notably under cisplatin treatment, enriches drug-tolerant persister (DTP) populations with mesenchymal (MES) properties, we also observed transitions contributing DTP entry exit. Additionally, single-cell-derived clone experiments unveiled a spectrum heritable traits linked functional influencing behaviour. Mathematical modelling supports critical all cell phenotypes evolutionary adaptation. Collectively, our study depicts systems as key early cancer drivers adaptive through regulating multistability landscapes. insights underscore necessity decoding for advancing long-term therapeutic effectiveness.

Language: Английский

The evolutionary theory of cancer: challenges and potential solutions DOI
Lucie Laplane, Carlo C. Maley

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(10), P. 718 - 733

Published: Sept. 10, 2024

Language: Английский

Citations

13
Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal DOI Creative Commons
Ángel Fernández-Sanromán, Annika Fendler, Benjy J.Y. Tan

et al.

Cancer Discovery, Journal Year: 2025, Volume and Issue: unknown, P. OF1 - OF23

Published: Jan. 8, 2025

Abstract Although the key aspects of genetic evolution and their clinical implications in clear-cell renal cell carcinoma (ccRCC) are well documented, how features coevolve with phenotype tumor microenvironment (TME) remains elusive. Here, through joint genomic–transcriptomic analysis 243 samples from 79 patients recruited to TRACERx Renal study, we identify pervasive nongenetic intratumor heterogeneity, over 40% not attributable alterations. By integrating transcriptomes phylogenetic structures, observe convergent specific phenotypic traits, including proliferation, metabolic reprogramming, overexpression putative cGAS–STING repressors amid high aneuploidy. We also uncover a coevolution between T-cell repertoire, as longitudinal shift TME an antitumor immunosuppressive state, linked acquisition recurrently late ccRCC drivers 9p loss SETD2 mutations. Our study reveals clinically relevant hitherto underappreciated patterns ccRCC. Significance: Using samples, reveal recurrent exclusively governed by factors, depletion, receptor coevolution, potential repression, increased proliferation. These can aid management guide novel treatment approaches.

Language: Английский

Citations

1
The origin of novel traits in cancer DOI
Steven A. Frank, Itai Yanai

Trends in cancer, Journal Year: 2024, Volume and Issue: 10(10), P. 880 - 892

Published: Aug. 6, 2024

Language: Английский

Citations

6
The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity DOI
Mustafa Sibai,

Sergi Cervilla,

Daniela Grases

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(2), P. 115229 - 115229

Published: Jan. 24, 2025

Language: Английский

Citations

0
Breaking barriers: we need a multidisciplinary approach to tackle cancer drug resistance DOI Creative Commons
James Ingham, Jia-Ling Ruan, Matthew A. Coelho

et al.

BJC Reports, Journal Year: 2025, Volume and Issue: 3(1)

Published: Feb. 27, 2025

Abstract Most cancer-related deaths result from drug-resistant disease(1,2). However, cancer drug resistance is not a primary focus in development. Effectively mitigating and treating will require advancements multiple fields, including early detection, discovery, our fundamental understanding of biology. Therefore, successfully tackling requires an increasingly multidisciplinary approach. A recent workshop on resistance, jointly organised by Cancer Research UK, the Rosetrees Trust, UKRI-funded Physics Life Network, brought together experts cell biology, physical sciences, computational clinicians to these key challenges devise interdisciplinary approaches address them. In this perspective, we review outcomes highlight unanswered research questions. We outline emerging hallmarks discuss lessons COVID-19 pandemic antimicrobial that could help accelerate information sharing timely adoption discoveries into clinic. envisage initiatives drive greater interdisciplinarity yield rich dividends developing new ways better detect, monitor, treat thereby improving treatment for patients.

Language: Английский

Citations

0
Systemic inflammation in response to radiation drives the genesis of an immunosuppressed tumor microenvironment DOI
Lin Ma, Jian‐Hua Mao, Mary Helen Barcellos‐Hoff

et al.

Neoplasia, Journal Year: 2025, Volume and Issue: 64, P. 101164 - 101164

Published: April 4, 2025

Language: Английский

Citations

0
Epigenetic heritability of cell plasticity drives cancer drug resistance through one-to-many genotype to phenotype mapping DOI Creative Commons
Érica Aparecida de Oliveira, Salvatore Milite, Javier Fernández-Mateos

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 16, 2023

Abstract Cancer drug resistance is multi-factorial, driven by heritable (epi)genetic changes but also phenotypic plasticity. Here we dissect it perturbing colorectal cancer patient-derived organoids longitudinally with drugs in sequence. Combining longitudinal tracking, single cell ’omics, evolutionary modelling, and machine leaning, found that different targeted select for distinct subclones, supporting rationally designed sequences. The cellular memory was encoded as a epigenetic configuration, from which multiple transcriptional programmes could run, one-to-many (epi)genotype-to- phenotype map explains how clonal expansions plasticity manifest together. This may ensure subclones can exhibit phenotypes changing environments while still preserving the encoding their selective advantage. Chemotherapies instead entirely Inducing further chromosomal instability before application changed evolution not convergent programmes. Collectively, our data show genetic alterations are selected to “permissive epigenome” enabling

Language: Английский

Citations

4
Comprehending phenotypic plasticity in cancer and evolution DOI Creative Commons
Prakash Kulkarni, Ravi Salgia

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109308 - 109308

Published: March 1, 2024

Organisms as well cancer cells are adept at adapting to changes in the environment which they find themselves, by actively adjusting their phenotype. Phenotypic plasticity is a quantitative trait that confers fitness advantage organism tailoring its phenotype environmental circumstances. While it generally held new traits arise solely from genetic factors, emerging evidence indicates phenotypic also plays critical role both and evolution. Thus, understanding mechanisms underlie can not only provide insights into organismal evolution origin of novelty but result novel strategies therapeutics treat cancer. ability individual genotypes produce different phenotypes (phenotypic switching) response without involving changes.Research field burgeoning an often-asked question whether environmentally initiated precedes even facilitates adaptation, or cancer.It seems obvious although how populations organisms respond modified conditions adapt themselves persistence, adaptive remains contentious.While some evolutionary biologists argue impede adaptation shifting distribution population hence, shielding natural selection, others believe favors

Language: Английский

Citations

1
Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma DOI Creative Commons
Josephine Yates,

Camille Mathey-Andrews,

Jihye Park

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses cohort primary metastatic tumors, incorporating single-nuclei transcriptomic chromatin accessibility sequencing, along spatial profiling. We identified tumor microenvironmental features previously described to associate therapy response. five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, cycling which were associated differential epigenetic plasticity clinical outcomes, for inferred candidate transcription factor regulons. Furthermore, revealed diverse localizations cells expressing their transcriptional programs predicted significant interactions types. validated our findings three external single-cell RNA-seq bulk studies. Altogether, advance understanding heterogeneity, progression,

Language: Английский

Citations

1
Serial single-cell RNA sequencing unveils drug resistance and metastatic traits in stage IV breast cancer DOI Creative Commons
Kazutaka Otsuji, Yōko Takahashi, Tomo Osako

et al.

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: Oct. 3, 2024

Language: Английский

Citations

1