Screening heavy smokers by low-dose computed tomography (LDCT) can reduce lung cancer (LC) mortality, but defining the population that benefits most, a prerequisite for cost-effective screening, is challenging. In order...Screening heavy smokers by low-dose computed tomography (LDCT) can reduce lung cancer (LC) mortality, but defining the population that benefits most, a prerequisite for cost-effective screening, is challenging. In order to contribute to a more nuanced risk stratification of high-risk target populations, we developed and validated a blood-based protein marker model for LC. A two-stage design was implemented in this study, and the derivation set comprised 18 868 participants from the UK Biobank, which included 200 incident LC cases identified at 6 years of follow-up. The independent validation set included 101 LC cases identified at 6 years of follow-up. A total of 2025 protein markers measured by proximity extension assays available for both datasets were used for analysis. A risk prediction algorithm by least absolute shrinkage and selection operator regression with bootstrap method was developed in the derivation set and then externally evaluated in the independent validation set. The risk discriminatory performance of the protein marker model was compared with the established PLCO model, USPSTF 2020 guidelines and trial criteria used in different LDCT trials. The protein marker model comprising of four protein biomarkers-CEACAM5, CXCL17, MMP12, and WFDC2-outperformed the PLCO model, and the areas under the receiver operating curve (AUCs) for the protein marker model in the derivation and validation sets were 0.814 [95% confidence interval (95% CI), 0.785-0.843] and 0.814 (95% CI, 0.756-0.873), respectively. The addition of the protein marker model to the PLCO model increased the AUCs up to 0.056 and 0.057 and yielded up to 16 and 12 percentage points higher sensitivities to identify future LC cases compared to the LDCT trial criteria, in the derivation and validation sets, respectively. The protein marker model improves the selection of high LC risk individuals for LDCT screening and thereby enhances screening efficacy.
Thorat MA, Arbyn M, Baldwin D
… +16 more, Castells X, Hofvind S, Ivanus U, Senore C, Toes-Zoutendijk E, van der Aalst C, Canelo-Aybar C, Fernández-Sáenz FK, Feliu A, Zeeb H, Carvalho AL, D'Souza E, Ritchie D, Espina C, Lansdorp-Vogelaar I, DeCensi A
Several medical therapies modify the risk of developing certain cancers in an individual. The aim of this paper was to provide the scientific justification for the 5th edition of the European Code Against Cancer (ECAC5)...Several medical therapies modify the risk of developing certain cancers in an individual. The aim of this paper was to provide the scientific justification for the 5th edition of the European Code Against Cancer (ECAC5) recommendation on the use of hormone replacement therapy (HRT) and other drugs used at population scale, such as hormonal contraceptives and aspirin. HRT modifies the risk of developing certain cancers in an individual. Except for vaginal oestrogens, all forms of HRT are associated with an increased breast cancer risk; the risk of serous ovarian cancer and endometrial cancer may also be increased. Despite such an increase in cancer risk, HRT often remains the only option for the management of certain menopausal symptoms for the restoration of quality of life and mental health. Therefore, the ECAC5 recommends using HRT for bothersome menopausal symptoms only after a thorough discussion with a healthcare professional and limiting its use for as short a duration as possible. On review of up-to-date evidence for hormonal contraceptives and aspirin, the ECAC5 Working Group elected not to make a recommendation for the average-risk general population regarding the use of these therapies.
Rondon-Lorefice I, Lopez JI, Ugalde-Olano A
… +14 more, Zufiaurre M, Astobiza I, Martin-Martin N, Bozal-Basterra L, Garcia-Longarte S, Zabala-Letona A, Rey S, Santos-Martin A, Unda M, Loizaga-Iriarte A, Graupera M, Nuciforo P, Carracedo A, Mendizabal I
Among the extensive genomic alterations in prostate cancer, phosphatase and tensin homolog (PTEN) deletion stands out as one of the most consistently observed events. PTEN loss in prostate tumors is primarily associated...Among the extensive genomic alterations in prostate cancer, phosphatase and tensin homolog (PTEN) deletion stands out as one of the most consistently observed events. PTEN loss in prostate tumors is primarily associated with cancer-cell proliferation and survival through the activation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) (PI3K-AKT-mTOR) signaling pathway. However, the use of PTEN as a robust biomarker in clinical practice is hampered by its complex epigenetic, transcriptional and post-translational regulation. In situ protein assessment by immunohistochemistry (IHC) captures PTEN protein status, but it does not report on associated tumor microenvironment remodeling. Here, we undertook an approach that combined PTEN immunoreactivity analysis with high-throughput transcriptional analysis to gain insights into the downstream functional effects of PTEN protein loss in primary tumors. Our extensive bioinformatic analyses highlighted stromal remodeling as a prominent cancer cell-extrinsic process associated with PTEN loss. By extending our transcriptomic computational strategy to Pten loss-driven murine prostate cancer, we validated the causal role of Pten in the stromal reaction observed in clinical specimens. Mechanistically, we provide experimental evidence for the activation of a paracrine program that encompasses enhanced transforming growth factor beta (TGF-β) signaling and that is compatible with the secretome of PTEN-deficient senescent cancer cells. Finally, our findings enable the sub-stratification of tumors with PTEN loss based on their senescence-associated stroma remodeling program to distinguish indolent from aggressive cases. Our study provides relevant biological context to the cellular and molecular alterations unleashed upon PTEN protein loss in prostate cancer.
Vandenhoeck J, De Meulenaere N, Vanpoucke T
… +10 more, Ibrahim J, Peeters D, Yogeswaran SK, Wen W, Van Schil P, Hendriks JMH, Raskin J, van Meerbeeck J, Van Camp G, Op de Beeck K
Pleural mesothelioma (PM) is a rare and aggressive cancer that often requires multiple diagnostic procedures before a definitive diagnosis can be made. To improve diagnostic accuracy, we developed a DNA methylation-based...Pleural mesothelioma (PM) is a rare and aggressive cancer that often requires multiple diagnostic procedures before a definitive diagnosis can be made. To improve diagnostic accuracy, we developed a DNA methylation-based biomarker assay capable of distinguishing PM from healthy pleura and other pleural pathologies. Using Infinium EPIC array data, we identified 744 hypermethylated CpG sites in PM as candidate biomarkers. These were validated in silico using external datasets, yielding a high mean AUC of 0.935. Clinical validation was performed using IMPRESS, a novel bisulfite-free methylation detection technique that enables simultaneous analysis of thousands of CpG sites. A two-step classifier approach was applied: the first model differentiated tumoral from nontumoral pleura with 89.2% sensitivity and 93.5% specificity, while the second model distinguished PM from pleural metastases with 85.2% sensitivity and 100% specificity. These results demonstrate that our methylation-based biomarker panel offers a highly accurate and minimally invasive tool for differentiating PM from other pleural conditions, potentially streamlining the diagnostic process and improving clinical decision-making.
Despite the use of conventional biomarkers and imaging methods for treatment monitoring of colorectal cancer (CRC) patients, limitations remain in detecting minimal residual disease and early relapse. Circulating tumor D...Despite the use of conventional biomarkers and imaging methods for treatment monitoring of colorectal cancer (CRC) patients, limitations remain in detecting minimal residual disease and early relapse. Circulating tumor DNA (ctDNA) offers a promising noninvasive and cost-effective alternative for monitoring disease progression and relapse, potentially improving patient outcomes. In this study, we developed a methylation-specific droplet digital PCR (MS-ddPCR) multiplex assay designed to detect ctDNA through a combination of tumor-specific and tissue-conserved methylation markers. Our objective was to evaluate the performance of this assay in patients with CRC and assess ctDNA dynamics as a prognostic tool in those with metastatic CRC (mCRC). The assay demonstrated high specificity (96.7%) and sensitivity in detecting ctDNA in both patients with localized tumors (64.4%) and mCRC (89.2%). Notably, ctDNA dynamics from baseline to after the first treatment cycle were significantly associated with progression-free survival (PFS) and overall survival (OS) in mCRC. Classifying patients based on ctDNA-RECIST (Response Evaluation Criteria in Solid Tumors) and the percent reduction in ctDNA fraction revealed pronounced differences in PFS and OS. Median PFS and OS were 11.4 and 35.3 months for good responders compared with 7.6 (HR = 1.71, 95% CI 0.9-3.25) and 18.4 (HR = 2.15, 95% CI 1.16-3.99) for poor responders, while patients with progressive disease had a median PFS and OS of 5.1 (HR = 4.36, 95% CI 1.91-9.92) and 6.85 (HR = 4.73, 95% CI 2.09-10.7) months. Our multiplex MS-ddPCR assay provides a sensitive, cost-effective approach for detecting and quantifying ctDNA in CRC patients, especially in metastatic disease. The ability to monitor ctDNA dynamics holds potential for early treatment response assessment, prognosis, and guiding personalized therapeutic strategies, making it a valuable tool for clinical practice.
Ilié M, Malapelle U, Alix-Panabières C
… +11 more, Andersen CL, Chlebowski S, Lake V, Lacoux C, Lespinet-Fabre V, Bordone O, Heeke S, Bontoux C, Heitzer E, Pantel K, Hofman P
Liquid biopsy has transformed molecular oncology by enabling noninvasive, real-time monitoring of cancer progression, treatment responses, and detection of minimal residual disease. Despite technological advances, educat...Liquid biopsy has transformed molecular oncology by enabling noninvasive, real-time monitoring of cancer progression, treatment responses, and detection of minimal residual disease. Despite technological advances, educational gaps, regarding standardized, comprehensive training for molecular pathologists, remain. To address these, a new educational program, the European Masters in Molecular Pathology (EMMP) developed a dedicated educational module aimed at providing pathologists with specialized competencies in liquid biopsy. In this perspective, we discuss how embedding liquid biopsy training within the integrative pathology framework, linking molecular diagnostics, histopathological findings, and clinical context, enhances diagnostic accuracy and therapeutic decision-making in the clinic. Furthermore, we emphasize the importance of decentralizing liquid biopsy expertise to local pathology units, reducing dependency on external commercial platforms, ensuring data sovereignty, and enabling rapid, cost-effective diagnostics. Finally, integrating health policy and ethical considerations within liquid biopsy education prepares future molecular pathologists to engage meaningfully in shaping policy frameworks that support equitable and sustainable clinical implementation of precision oncology. In summary, we propose the EMMP module as a comprehensive educational strategy for training molecular pathologists in the latest liquid biopsy technologies and advancements.
Breast cancer's global prevalence underscores a critical need for novel biomarkers to guide treatment and improve patient outcomes. Biomarker discovery historically focused on mutations in protein coding regions, compris...Breast cancer's global prevalence underscores a critical need for novel biomarkers to guide treatment and improve patient outcomes. Biomarker discovery historically focused on mutations in protein coding regions, comprising merely 1% of the genome. However, with advances in whole-genome sequencing, the functional significance of the noncoding genome-comprising the remaining 99%-has become increasingly evident. Noncoding regions play a vital role in regulating gene expression, and mutations within these regions have been associated with cancer risk, progression, and treatment response. This Review compiles and synthesizes current knowledge on cis-regulatory alterations (promoters/enhancers) and long noncoding RNAs (lncRNAs) in breast cancer. Key examples include promoter mutations [e.g., rs2279744 (Mouse double minute 2 homolog gene; MDM2)], enhancer mutations [e.g., rs4784227 (thymocyte selection-associated high mobility group box family member 3 gene; TOX3)], and lncRNAs [e.g., HOX transcript antisense intergenic RNA (HOTAIR)] linked to progression, metastasis, and poor survival. Integrating preclinical (in vitro, in vivo) and clinical findings, we emphasize the biomarker and therapeutic potential of these noncoding alterations. This Review also critically identifies the pressing need for more specific functional validation studies to fully elucidate their mechanistic roles. This emerging field offers promising opportunities to advance personalized medicine and refine prognostic/predictive strategies for breast cancer patients.
Fernández-Sáenz FK, de la Torre-Perez L, Baldwin DR
… +10 more, van der Aalst C, Thorat M, Ritchie D, Carvalho AL, Espina C, Solà I, Canelo-Aybar C, Pissinis MM, Alonso-Coello P, Pinto ACPN
Low-dose computed tomography (LDCT) screening is increasingly used for early lung cancer detection targeted to high-risk populations. Quantifying overdiagnosis, its potential harms, and economic consequences is important...Low-dose computed tomography (LDCT) screening is increasingly used for early lung cancer detection targeted to high-risk populations. Quantifying overdiagnosis, its potential harms, and economic consequences is important. We assessed the magnitude, harms, and economic impact of lung cancer overdiagnosis from LDCT screening in high-risk populations. We synthesized evidence from eight randomized trials involving 84,660 participants. LDCT may increase overdiagnosis compared to no screening (relative risk [RR] 1.05; 222 additional cases per 100 000 people screened; low certainty). Compared to chest x-ray (CXR), LDCT likely slightly increases overdiagnosis (RR 1.01; 63 additional cases per 100 000 people screened; moderate certainty). The proportion of overdiagnosed cancers is 0.07 (7000 more lung cancers overdiagnosed per 100 000 lung cancers detected; low certainty) when compared to no screening, and 0.01 compared to CXR (1000 more lung cancers overdiagnosed per 100 000 lung cancers detected; moderate certainty). In terms of cost, LDCT resulted in an additional societal burden of €2,026,422.00 per 100 000 individuals screened compared to no screening. The magnitude of overdiagnosis in LDCT screening is likely low compared to CXR.
Advanced urothelial carcinoma (UC) requires new therapeutics beyond chemo- and immunotherapies. Clinical trials with PARP inhibitors (PARPi), particularly in Cisplatin-treated UC, yielded limited response. Biomarker-base...Advanced urothelial carcinoma (UC) requires new therapeutics beyond chemo- and immunotherapies. Clinical trials with PARP inhibitors (PARPi), particularly in Cisplatin-treated UC, yielded limited response. Biomarker-based patient selection (apart from BRCAness) or combination treatment may increase efficacy. To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. RNA sequencing of PARPi-treated UC lines revealed few common targets and a different impact on immune response. By analysis of experimental and public clinical data, we identified new UC-specific PARPi response predictors SLFN5, SLFN11, and OAS1. We investigated a new combination treatment using PLX51107, an epigenetic BET protein inhibitor, to increase PARPi efficacy. The Talazoparib + PLX51107 combination had a strong synergistic impact on UC cells and organoids, including Cisplatin-resistant cells, allowing dose reduction to spare benign cells. Mechanisms of synergism targeted homologous recombination repair, DNA replication, and apoptosis regulation. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.
Cancer is a highly heterogeneous disease, with many cancers containing multiple distinct subclones. While subclones are often seen as competitors (survival of the fittest), intratumor heterogeneity can also offer direct...Cancer is a highly heterogeneous disease, with many cancers containing multiple distinct subclones. While subclones are often seen as competitors (survival of the fittest), intratumor heterogeneity can also offer direct benefits to the tumor through cooperation between different clones. This has important clinical implications, as interdependent populations may present therapeutic vulnerabilities. Here, we review existing evidence for clonal cooperativity to address key questions and outline future developments based on six overarching principles: (a) secreted factors are important mediators of clonal cooperation; (b) (very) small subclones can significantly affect tumor behavior; (c) both genetic and nongenetic heterogeneity are substrates for cooperation; (d) nonmalignant cells from the tumor microenvironment can act as cooperating partners; (e) clonal cooperation occurs throughout different stages of cancer, from premalignancy to metastasis; and (f) clonal cooperation can promote therapy resistance by protecting otherwise sensitive populations. Together, these principles suggest clonal cooperation as an important mechanism in cancer. Lastly, we discuss how novel technological developments could address remaining gaps to open up new therapeutic strategies that exploit clonal cooperativity by targeting the tumor's weakest link.
Son J, Remsing Rix LL, Fang B
… +11 more, Welsh EA, Bremer NV, Foglizzo V, Roa P, Sigcha-Coello N, Liao Y, Haura EB, Drilon A, Koomen JM, Cocco E, Rix U
Rearranged during transfection (RET) fusions drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite new selective RET tyrosine kinase inhibitors (TKIs), resistance usually occu...Rearranged during transfection (RET) fusions drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite new selective RET tyrosine kinase inhibitors (TKIs), resistance usually occurs and is often driven by RET-independent bypass mechanisms. Previous studies have implied crosstalk between RET and proto-oncogene tyrosine-protein kinase SRC, but the anticancer effects of targeting SRC combined with selective RET TKIs, and the underlying molecular mechanisms involved, are not fully understood. Our results show that the multitargeted SRC TKI dasatinib significantly enhanced the efficacy of RET TKIs in RET fusion-positive (RET) NSCLC and PTC cells. Genetic rescue experiments validated that the combination effects between RET TKIs and dasatinib were indeed SRC-dependent. Phosphoproteomics analysis and validation using selective inhibitors and small interfering RNAs (siRNAs) determined that synergy was primarily mediated by suppression of downstream serine/threonine-protein kinase PAK signaling, with contributions from AKT and ribosomal protein S6. Importantly, synergy was also observed with eCF506 (NXP900), a next-generation clinical SRC inhibitor. Finally, both SRC TKIs restored sensitivity in selpercatinib-resistant RET PTC cells. These results elucidate RET and SRC signaling crosstalk in RET NSCLC and PTC, suggesting that co-inhibiting SRC has clinical potential in TKI-naïve and -resistant RET cancers.
Metastatic colorectal cancer (mCRC), particularly microsatellite stable (MSS) cases, often exhibits limited responsiveness to immunotherapy, leaving chemotherapy as the primary treatment option. While chemotherapy effect...Metastatic colorectal cancer (mCRC), particularly microsatellite stable (MSS) cases, often exhibits limited responsiveness to immunotherapy, leaving chemotherapy as the primary treatment option. While chemotherapy effectively targets tumor cells, its impact on the broader mutational landscape, including passenger mutations in large genes such as Titin (TTN), remains poorly understood. Passenger mutations, traditionally deemed biologically inert, may reflect tumor mutational burden (TMB) and influence treatment outcomes. In our study involving whole exome sequencing of paired primary and metastatic tumor samples from 22 mCRC patients, recurrent driver mutations in APC, KRAS, and TP53 were consistently observed. However, passenger mutations in large genes, particularly TTN, were notably enriched in chemonaïve specimens and associated with higher TMB. Chemotherapy-treated samples exhibited a significant reduction in these mutations, suggesting selective depletion of hypermutated subclones. Our findings demonstrate that chemotherapy may selectively reduce passenger mutations in mCRC, potentially influencing the persistence of hypermutated subclones. This highlights the potential role of passenger mutation patterns and TMB as biomarkers for treatment response and raises the hypothesis that they could help guide immunotherapy considerations for patients with MSS mCRC.
Maiuthed A, Huebner K, Erlenbach-Wuensch K
… +8 more, Hampel C, Thalheim D, Vial-Roehe A, Nutho B, Merkel S, Hartmann A, Chanvorachote P, Schneider-Stock R
Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance. The role of cytoplasmic cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) in CSC biology remains unclear. Since cytoplasmic p21 correl...Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance. The role of cytoplasmic cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) in CSC biology remains unclear. Since cytoplasmic p21 correlated with advanced stage and metastasis in colorectal cancer (CRC) patients, we investigated its causal role in CSC features in vitro and in vivo. Cytoplasmic p21 increased spheroid formation and CD133 expression in a mechanism partly dependent on AKT activation. Phosphomimetic p21 (p21) enhanced spheroid growth, CD133, and stemness factors (Oct3/4, Nanog, Sox2), whereas nuclear p21 (p21) reduced them. Immunoprecipitation, proximity ligation assays, and in silico modeling demonstrated that cytoplasmic p21 interacts with the NFκB-IκB complex, promoting NFκB release and activation. Consequently, NFκB targets BCL-xL and COX2 were upregulated in p21- and AKT CRC cells in vitro and in a chorioallantoic membrane (CAM) model, supporting their role as downstream effectors of cytoplasmic p21. Our findings uncover a new function of cytoplasmic p21 in regulating CSC properties through NFκB modulation. Screening p21 subcellular localization may stratify CRC patients with high metastatic risk providing a basis for CSC-targeted therapeutic strategies.
Tolotto V, Gualandi N, Cortolezzis Y
… +11 more, Picco R, Colitti M, D'Este F, Gani M, Hancock WW, Terrosu G, Degrassi C, Agostini F, Brancolini C, Xodo LE, Di Giorgio E
Epigenetic plasticity and large-scale chromatin remodeling characterize tumor evolution and the emergence of subclones resistant to conventional therapies. Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDA...Epigenetic plasticity and large-scale chromatin remodeling characterize tumor evolution and the emergence of subclones resistant to conventional therapies. Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) control the targeted recruitment of chromatin remodeling complexes, making them attractive therapeutic targets in oncology. In this study, we found that HDAC4 is degraded by the proteasome in cancer cells with impaired DNA repair by homologous recombination and after oxaliplatin (OXPT) treatment. Genetic screening identified FBXW7 as the E3 ligase responsible for HDAC4 degradation. FBXW7 loss-of-function mutations are frequently found in patients with colorectal cancer (CRC) and were found associated with the development of resistance to OXPT. Forced degradation of Class IIa HDACs using a PROTAC-based compound restored OXPT sensitivity in FBXW7-mutated CRC cells, patient-derived organoids (PDOs), and mice. Mechanistically, removal of HDAC4 in FBXW7-mutated CRC treated with OXPT recreated an epigenetic state comparable to OXPT-sensitive cells. Furthermore, patient profiling based on the epigenetic state of the super-enhancers controlled by HDAC4 successfully identified a priori CRC patients resistant to platinum. This study supports HDAC4 as a key mediator of oxaliplatin resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined super-enhancer repertoire as part of the process of OXPT resensitization.
The genomic instability associated with cancer can result in the formation of extrachromosomal circular DNA (eccDNA), which contributes to tumor heterogeneity, gene amplification, tumor evolution, and drug resistance. Ho...The genomic instability associated with cancer can result in the formation of extrachromosomal circular DNA (eccDNA), which contributes to tumor heterogeneity, gene amplification, tumor evolution, and drug resistance. However, most studies on eccDNA have been conducted on tumor tissue or cancer cell lines, and limited research has been done on eccDNA in plasma. In this study, we investigated eccDNA in non-small cell lung cancer (NSCLC) by sequencing plasma eccDNA from 32 epidermal growth factor receptor (EGFR)-mutated NSCLC patients before and during treatment with osimertinib, as well as plasma eccDNA from five healthy individuals. Plasma eccDNA was identified in all samples but with significantly higher levels in cancer patients than healthy controls. EGFR-overlapping eccDNA, eccDNA that contains part of or the whole EGFR gene, was detected in the majority of samples both at baseline and during treatment. High levels of EGFR-overlapping eccDNA during osimertinib treatment were associated with significantly shorter progression-free survival and overall survival. Plasma eccDNA represents a newly identified type of biomarker for monitoring treatment efficacy.
RAS oncoproteins have been considered undruggable for decades. However, recent advances have led to the development of a large variety of RAS inhibitors. While a multitude of drugs is currently under clinical evaluation,...RAS oncoproteins have been considered undruggable for decades. However, recent advances have led to the development of a large variety of RAS inhibitors. While a multitude of drugs is currently under clinical evaluation, some of them have already been approved in specific contexts, leading to a continuous improvement of available therapeutic options for patients with RAS-mutant cancers. In this Viewpoint, we discuss different classes of RAS inhibitors, with emphasis on those that are currently tested in the clinic including allele-specific KRAS, panKRAS, and panRAS inhibitors. We also address determinants of response to RAS inhibition such as the tumor context or potential resistance mechanisms. Finally, we provide an outlook on the future of RAS targeting, which is likely to involve combination therapies. The rapid approval of several RAS inhibitors reflects the urgency to develop novel therapeutic strategies to treat RAS-mutant cancers.
Reactive oxygen species (ROS) are a diverse group of molecules that serve as both essential signalling mediators and potential drivers of oxidative stress. In tumours, ROS influence critical processes such as proliferati...Reactive oxygen species (ROS) are a diverse group of molecules that serve as both essential signalling mediators and potential drivers of oxidative stress. In tumours, ROS influence critical processes such as proliferation, angiogenesis, metabolic adaptation and therapy resistance. These processes are further modulated by reduced oxygen availability (hypoxia), a defining feature of many solid tumours that can alter redox balance and cellular signalling. The interplay between ROS and hypoxia is highly dynamic, with both factors shaping tumour behaviour in complex and often unpredictable ways. Accurately measuring ROS and tumour oxygenation remains a significant challenge due to their transient nature and variability in levels across different tumour types. In this guide, we provide a comprehensive update on the dynamic interaction between ROS and hypoxia in tumours, evaluate current strategies for ROS detection and discuss emerging therapeutic approaches that target redox vulnerabilities in cancer. Understanding the intricate relationship between ROS and hypoxia is crucial for refining therapeutic strategies and improving patient outcomes.
Cancer-associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their pro- and antitumorigenic functions, which are attributed to specializations in CAF subtypes. A precise targeting of spec...Cancer-associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their pro- and antitumorigenic functions, which are attributed to specializations in CAF subtypes. A precise targeting of specific subtypes would be required to design therapies that effectively modulate CAF phenotypes, necessitating translatable model systems to support target discovery efforts. However, not only is our knowledge of CAF heterogeneity in solid tumors lacking, particularly in pancreatic tumors, but the translatability of CAF models has also not been rigorously evaluated. Here, we develop a coculturing model with primary CAFs and immortalized tumor cell lines that can reliably represent CAF phenotypes observed in tumors, with correlations to immuno-resistant and immunomodulatory phenotypes. Using single-cell transcriptomics, we characterize the CAF subtype heterogeneity in the in vitro CAF cell lines isolated from pancreatic cancer patients and investigate the impact of perturbing potential stromal genes on different CAF subtypes. We also infer the continuum of state changes underlying the interconvertibility of CAF subtypes. Finally, we use immortalized CAF cell lines to perform single-cell CRISPR perturbations of stromal targets, revealing the subtype-specific effects of perturbations and the impact of model-type selection on the translatability of insights.
Martinez-Romero A, Martinez-Larrinaga A, Grego-Bessa J
… +9 more, Garcia-Longarte S, van Splunder H, Astobiza I, Ercilla A, Bozal-Basterra L, Mendizabal I, Villacampa P, Carracedo A, Graupera M
Pericytes are intrinsic components of vessels that regulate vascular stability and permeability. Aberrant vascularization is a hallmark of cancer, although the contribution of pericytes to this process is poorly understo...Pericytes are intrinsic components of vessels that regulate vascular stability and permeability. Aberrant vascularization is a hallmark of cancer, although the contribution of pericytes to this process is poorly understood. Here, we undertook a combined computational and experimental approach to identify the molecular reprogramming of prostate pericytes during cancer pathogenesis and progression. Analysis of human prostate cancer and murine models showed that prostate tumors exhibit a disequilibrium between endothelial and pericyte content with prognostic potential. Deeper molecular analysis revealed that there is no overt loss of pericytes in prostate tumors but rather a dysfunction that is concomitant with altered expression of a subset of cellular markers. We translate this finding into a simplified signature that discriminates pericyte abundance versus function. Leveraging single-cell RNA sequencing data, we find that TGF-β governs the molecular changes that underlie pericyte dysfunction in tumors. This mechanism is associated with reduced expression of contractility markers, enlargement of the vascular lumen, and increased permeability in prostate cancer. This study revisits the paradigm of the reduced number of pericytes in favor of their dysfunction in tumors and the importance of paracrine signaling in this process.