The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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  1. Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides
  2. Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function
  3. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment
  4. Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
  5. Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients
  6. Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse
  7. Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells
  8. Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme
  9. Cancer Mutations Converge on a Collection of Protein Assemblies to Predict Resistance to Replication Stress
  10. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening
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1Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides

Huang, D., Zhu, X., Ye, S. et al. Nature. 625, 593-602 (2024).
doi: 10.1038/s41586-023-06834-7.

Summary of the findings

Immunotherapy controls tumour progression by re-activating the anti-tumour immunity of cancer patients, which has developed rapidly and made revolutionary breakthroughs in malignancies such as melanoma and leukaemia. However, immunotherapy is less effective in solid tumours, which might be attributed to the lack of tumour-specific antigens (TSAs). Previous studies have mainly focused on nonsynonymous mutations in the protein-coding genome to identify TSAs. However, most solid tumours showed low mutational burden, which could not generate efficient neoantigens to elicit anti-tumor immunity.
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In this article, the authors identified TSAs derived from the open reading frames of tumour-specific circRNAs by matching the mass spectrometric analysis on human leukocyte antigen class I (HLA-I) immunoprecipitates of breast cancer tissues with whole-exome sequencing, RNA sequencing and ribosome sequencing data of tumour samples and their adjacent normal tissues. CircFAM53B, which encodes antigenic peptides distinct from its linear counterpart and bound to HLA-I, could elicit robust anti-tumour immune response in vitro and in patient-derived xenograft (PDX) mouse models. Moreover, vaccination with antigenic circRNA or its encoded cryptic antigenic peptides could effectively control the tumour growth and metastasis by eliciting strong antigen-specific immune responses in immunocompetent mice bearing breast cancer or melanoma. This research demonstrated that tumour-specific circRNAs are capable of eliciting anti-tumour immune responses by encoding cryptic antigenic peptides.
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The tumour-specific circRNAs encoded cryptic antigenic peptides that were distinct from their linear counterparts and could be presented to HLA-I molecules. These circRNAs and their encoded cryptic peptides could drive antigen-specific T cells immune response, which might be exploit as a feasible strategy for tumour vaccines. This figure was created with BioRender.com.

Future impact

This research demonstrated that noncanonical translation of tumour-specific circRNAs are capable of eliciting anti-tumour immune responses at the initial step of priming tumour antigen-specific T cells and thereby enhance effector immune cell deployment, highlighting the therapeutic potential of vaccination exploiting tumour-specific circRNAs or their encoded cryptic antigenic peptides in malignant tumours.
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Read more in Nature

2Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function

Bercier, P., Wang, Q.Q., Zhang, J. et al. Cancer Discovery. 13(12), 2548-2565 (2023).
doi: 10.1158/2159-8290.CD-23-0453.

Summary of the findings

Arsenic trioxide (ATO) is a potent therapy of acute promyelocytic leukemia (APL), curing up to 70% patients as a single agent. APL is driven by the PML/RARA fusion protein, which is targeted for degradation by ATO through binding to its PML moiety. ATO modifies the nuclear distribution and stability of PML/RARA and normal PML proteins. It precipitates their self-assembly into nuclear bodies (NBs), initiating their post-translational modification by SUMO and ultimately their clearance. Yet, how ATO actually binds PML and drives NB assembly remained somehow unsettled. Arsenic efficiently binds sulfur atoms and this work has identified a critical cysteine residue in PML B2 as the key ATO target. PML B-box-2 structure reveals an alpha helix driving hydrophobic trimerization which positions these cysteines to form a trio constituting an ideal arsenic binding site. Arsenic-binding freezes this trimeric interaction, altering PML NB assembly dynamics. Impeding trimer formation (as seen with mutations observed in rare ATO-resistant APL patients) or the key cysteine residue impedes ATO-driven NB assembly, PML sumoylation and PML-RARA degradation. Overall, this study clarifies the interplay between ATO and PML, which underlies APL cure.
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PML B2 self-assembles as a homo-trimer which contributes to PML nuclear body (NB) formation. Arsenic trioxide (ATO) binds to 3 critical cysteine residues positioned by the trimer, freezing NB dynamics and enforcing NB formation. This triggers sumoylation/ degradation of PML-RARA, driving acute promyelocytic leukemia (APL) cure.

Future impact

PML modulates response to multiple stress in vivo, including oxidative stress. The cysteine trio identified here represents the PML redox sensing center, highjacked by ATO during APL therapy. PML is required for efficient therapy response to other drugs that ATO. Exploring PML mutants defective for oxidative stress sensing could shed a new light on the role of therapy-driven oxidative stress in drug response.

3Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment

He, X.Y. et al. Cancer Cell 42(3), 474-486.E12 (2024).
doi: 10.1016/j.ccell.2024.01.013.

Summary of the findings

Chronic stress increases the likelihood of cancer patients developing metastasis (i.e., the spread of cancer to other parts of the body) and reduces the chances of survival, though the exact reasons remain unclear. This study investigated how chronic stress impacts metastasis, and identified stress-induced changes in the microenvironment mediated by neutrophils as a key mechanism.
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Using mouse models, a 2- to 4-fold increase in metastasis to the lungs or spleen was observed when mice were exposed to chronic stress. Chronic stress altered the lung microenvironment, with the accumulation of the extracellular matrix protein fibronectin and reduced T cell infiltration. Chronic stress majorly affected neutrophils: increasing their lung infiltration, disrupting their normal circadian rhythms, and inducing neutrophil extracellular trap (NET) formation. Mice with neutrophils that lacked the classical receptor for the glucocorticoid stress hormone did not produce NETs nor displayed increased metastasis after chronic stress exposure. Additionally, digesting the NETs with an enzyme called DNase I, prevented the metastasis caused by chronic stress.
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In conclusion, glucocorticoid release during chronic stress prompts NET formation, establishing an environment that fosters spread of cancer. Targeting NETs could potentially prevent metastasis recurrence in cancer patients experiencing chronic stress.
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Chronic stress significantly altered the lung microenvironment, with an accumulation of fibronectin, a reduction in T cell infiltration, and an increase in neutrophil infiltration. Mechanistically, glucocorticoids released during chronic stress shifted the normal circadian rhythm of neutrophils by regulating the expression of circadian-related genes and caused increased NET formation. Targeting GR in neutrophils or digesting NETs with DNase I prevented chronic stress from causing fibronectin accumulation and inducing lung metastasis. GC: glucocorticoid, CRH: corticotropin-releasing hormone. ACTH: adrenocorticotropic hormone, NET: neutrophil extracellular trap, GR: glucocorticoid receptor. **Reprinted from Cancer Cell, 42(3), He, X.Y. et al., Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment, 474-486.E12., Copyright (2024), with permission from Elsevier.

Future impact

Understanding the impact of chronic stress on metastasis and the specific roles of neutrophils in driving stress-associated metastasis can inform the development of strategies to prevent or manage the metastatic spread of cancer cells. The development of drugs to inhibit NET formation could potentially benefit patients at risk of metastasis, as such drugs may slow or stop the spread of cancer.
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Together, the findings of the study provide valuable insights into the relationship between stress, the immune system, and cancer progression. It highlights the importance of managing stress in cancer treatment and prevention.
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4Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells

Wang, Z. et al. Cancer Discovery 14(2), 362-379 (2024).
doi: 10.1158/2159-8290.CD-23-0402.

Summary of the findings

The gene that encodes the tumor suppressor TP53 (called Trp53 in the mouse or p53 generically) is the most commonly mutated gene in human cancer. Mutant TP53 proteins have been reported to drive malignant transformation and sustain tumor growth as well as evasion from therapy via loss-of-function (LOF), dominant-negative effects (DNE) and/or gain-of-function (GOF) activities. However, the relative contributions of these three effects to tumorigenesis are controversial. Here, by using a doxycyclin-inducible CRISPR/Cas9 genome editing system, we found that the removal of >10 different TP53 mutants in 15 human cancer cell lines of diverse cellular origin and in patient colon cancer-derived organoids did not impact their survival, proliferation or chemotherapeutic response in culture. Similarly, there was no effect on the growth of human and murine cancer cell lines or the metastasis of murine cancer cell lines in vivo in mice when mutant TP53 was deleted. Our functional data was consistent with previous studies since mining the DepMap database showed no effects on viability of removing 158 different TP53 mutants in almost 400 human cancer cell lines. These results suggest that the GOF effects of mutant TP53 are not essential for the growth, metastasis or therapy evasion of cancers.
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Since our data indicated that the LOF of wild-type (wt) TP53 was contributing to tumor growth, we used CRISPR mediated homology directed repair to convert mutant TP53 to wt TP53 sequence in select human cancer cell lines. The expression of wt TP53 led to rapid death of the tumor cells in vitro. This suggests that drugs that can restore wt functions to mutant TP53 proteins would have therapeutic potential for mutant TP53 cancers.
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Future impact

Our findings across a panel of human cancer cell lines provide important insights into how mutant TP53 contributes to tumorigenesis that inform on therapeutic approaches for mutant TP53 cancers. Our data indicate that it is the LOF of wt TP53 rather than putative GOF effects of mutant TP53 that are permitting tumor growth. We therefore expect that drugs that act to restore wt TP53 functions to mutant TP53 proteins should stop the growth of or kill such cancer cells, thereby exerting substantial therapeutic impact.

5Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients

Radtke, A. J., Postovalova, E. et al. Cancer Cell 42(3), 444-463.E10 (2024).
doi: 10.1016/j.ccell.2024.02.001.

Summary of the findings

Follicular lymphoma (FL) is a generally incurable cancer that evolves from developmentally blocked B cells. One of the greatest challenges for the treatment and management of FL is the significant clinical heterogeneity observed both within and across patients. The majority of patients experience an indolent clinical course characterized by a relapsing and remitting disease over many years; however, approximately 20% of patients present with an aggressive clinical course with increased risk for premature death.

In this article, the authors used advanced sequencing and imaging technologies to provide a comprehensive examination of the FL tumor microenvironment (TME) from patients enrolled in a prospective clinical trial. By integrating multi-omic technologies, Radtke, Postovalova, and colleagues identified enhanced B cell receptor (BCR) signaling in the tumor B cells of high-risk FL patients suggestive of BCR engagement in the TME. The authors additionally reported the enrichment of distinct histological patterns in high-risk FL patients including alterations in the shape and size of neoplastic follicles and enhanced stromal remodeling. Importantly, these distinguishing features were observed an average of 20 months before first progression and first relapse in an untreated patient cohort, providing a potential means for early patient stratification by risk.

**Reprinted from Cancer Cell, Volume 42, Issue 3, Radtke, A. J. et al., Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients, 444-463, Copyright Elsevier (2024), with permission from Cancer Cell

Future impact

Through detailed assessment of the FL TME at single cell and spatial resolution, this work discovered a new cell type now confirmed by others: dendritic cell–specific ICAM-3–grabbing nonintegrin (DC-SIGN)–expressing follicular dendritic cells. Future impact of this work includes extending these findings to a larger clinically annotated cohort to evaluate whether the histological patterns described here can reliably predict disease behavior. Furthermore, this work may inform treatment strategies for high-risk FL patients such as anti-fibrotic agents or therapies that inhibit DC-SIGN-induced BCR signaling.

6Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse

Chen, M. et al. Cell Rep Med, 5(3), 101471 (2024).
doi: 10.1016/j.xcrm.2024.101471.

Summary of the findings

Drug-tolerant persisters (DTPs) are a rare subset of cancer cells that evade death from targeted or chemotherapy by reversible withdrawal from the cell cycle through non-genetic mechanisms. Many studies have focused on the mechanisms through which DTP emerge, but far fewer studies have been directed at identifying the acquired vulnerabilities of DTPs. Such vulnerabilities could be exploited for their selective eradication to delay tumor relapse.
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In this manuscript, Chen et al. used a kinome-based CRISPR screen and compound screen, to identify inhibition of bromodomain and extra-terminal domain (BET) proteins as a way to selectively reduce DTP populations across various cancer types. It was already known that DTPs have increased levels of Reactive Oxygen Species (ROS). The authors found that inhibition of BET proteins further increases ROS to toxic levels in DTPs through suppression of anti-oxidant genes like GPX2, ALDH3A1, and MGST1. In vivo experiments demonstrated that BET inhibitors effectively delayed tumor recurrence in melanoma and lung cancer models. In summary, the study by Chen et al. suggests that combining standard of care therapy with BET inhibitors to eliminate residual DTP cells is a promising therapeutic strategy.
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This figure was created with BioRender.com.

Future impact

There are multiple related cell states that resemble DTPs, including senescence, dormancy, quiescence and diapause. Gold standard biomarkers to discriminate between these cell states are currently lacking. Finding the specific vulnerabilities of these different non-cycling cells through the approach used here may be a viable strategy to unambiguously identify these cells. For instance, using the same approach as described here, senescent cancer cells have been shown to be very sensitive to death receptor activation, while the current manuscript shows that DTPs are less responsive to this cell death trigger.
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7Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells

Guan, X. et al. Nature 627, 646–655 (2024).
doi: 10.1038/s41586-024-07121-9.

Summary of the findings

Cancer immunotherapy, specifically checkpoint blockade of PD-(L)1 is designed to overcome mechanisms of cancer immune evasion. However, despite the significant advances achieved with checkpoint blockade therapies, there remains a pressing need to improve response rates, overcome resistance mechanisms, and enhance safety profiles.
The Phase 2 CITYSCAPE study tested blockade of TIGIT, another immune checkpoint, and demonstrated improved patient outcomes when tiragolumab (anti-TIGIT) was administered with atezolizumab (anti-PD-L1), as compared to atezolizumab alone in patients with untreated non-small cell lung cancer.
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In this paper, the authors show that this enhanced efficacy was surprisingly associated with a high baseline of intratumoral macrophages (TAMs) and regulatory T (Treg) cells, both cell types typically associated with resistance mechanisms to PD-(L)1 blockade. Further, serum protein profile suggested that macrophage activation post treatment was associated with improved clinical outcomes, indicating a differentiated mechanism of action with a synergistic effect between the two therapies.
Preclinical investigations using murine tumor models suggested functional engagement of the Fc domain of anti-TIGIT antibodies was crucial in activating tumor and circulating myeloid cells synergistically with anti-PD-L1, and converting CD8+ T cells to a more memory-like phenotype.
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Together, these findings suggest that this dual checkpoint blockade leads to better tumor control by (1) Improving the quality of the immune response, expanding tumor-specific, longer-lived T-cells resistant to exhaustion and (2) Reshaping the tumor microenvironment to become less suppressive and more proinflammatory (upregulating antigen presentation genes in TAMs and downregulating immune suppressive genes in T-regs).
This research underscores the potential of TIGIT blockade and the value of understanding intricate immune mechanisms for optimizing treatment strategies.
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8Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme

Sosinsky, A., Ambrose, J., Cross, W. et al. Nature Medicine 30, 279-289 (2024).
doi: 10.1038/s41591-023-02682-0.

Summary of the findings

Over the last decade, cancer incidence rates have continued to rise, underscoring the need for advanced molecular cancer testing and targeted therapies. The 100,000 Genomes Project, a UK government initiative, aimed to sequence entire genomes of patients with cancer and integrate this data with their longitudinal health records. This study analysed 13,880 tumour-normal sample pairs, providing comprehensive genomic data across 33 tumour types. The findings demonstrated the ability of whole genome sequencing (WGS) to detect a range of clinically significant mutations, including somatic variants, copy number alterations, and gene fusions, within a single test. Additionally, germline variants associated with cancer risk and pharmacogenomic markers were identified. Findings were linked to real-world clinical outcomes, showing the predictive value of certain pangenomic markers, such as tumour mutation burden (TMB) and homologous recombination deficiency (HRD), for treatment responses. The study supports the integration of WGS in clinical cancer care and has led to the establishment of the NHS Genomic Medicine Service for routine genomic testing in the UK.
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Future impact

The study highlights the importance of comprehensive genomic profiling in improving cancer diagnosis and treatment, potentially transforming cancer clinical care and enabling personalised medicine. The integration of genomic data with real-world clinical outcomes will continue to refine biomarker selection, improve prognostic and predictive evaluation, and support regulatory decision-making. Future research will likely focus on integrating multimodal molecular data to maximise the benefits of precision cancer care.

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9Cancer Mutations Converge on a Collection of Protein Assemblies to Predict Resistance to Replication Stress

Zhao, X., Singhal, A. et al. Cancer Discovery, 14(3), 508-523 (2024).
doi: 10.1158/2159-8290.CD-23-0641.

Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer

Summary of the findings

Many conventional chemotherapeutic agents, such as cisplatin, gemcitabine, olaparib, etc. act by causing DNA replication stress. However, drug resistance often arises through multiple molecular mechanisms limiting the therapeutic potential of such therapies.

Using data from affinity purification mass spectrometry integrated with genomics data sets from current clinical cancer gene panels and human cancer cell lines, and a combination of “interpretable” machine learning and multitask learning Zhao et al developed a method to predict resistance to chemotherapeutics that induce replication stress based on genetic alterations identified in tumour samples. By projecting individual gene alterations onto protein assemblies associated with cancer, the authors identified 41 molecular assemblies, encompassing alterations in hundreds of genes, that modulate treatment response to replication stress-inducing agents. As an example, the authors highlight the prognostic potential of the RTK–JAK–STAT assembly, comprising alterations in more than eight different genes, for predicting response to cisplatin.

By highlighting molecular assemblies associated with multi-drug resistance, this study by Zhou et al opens new opportunities for further research into the molecular mechanisms underlying genetic drug resistance to replication-stress-inducing agents and further drug development.

Read more in Cancer Discovery

10A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening

Chung, D.C. et al. NEJM 390(11), 973-983 (2024).
doi: 10.1056/NEJMoa2304714.

Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer

Summary of the findings

Colorectal cancer is one of the most frequently encountered forms of cancer and one of the leading causes of cancer-related deaths. Although very efficient screening procedures are in place, almost 40% of the US population eligible does not benefit from the available screening procedures due to various reasons including costs and invasiveness. This is reflected in the fact that up to 76% of colorectal cancer-related deaths in the US occur in individuals who were not screened as recommended.

In this paper, Chung et al. describe a blood test that could detect malignant and pre-malignant colorectal lesions and could be performed as part of a routine healthcare encounter for people over 45. In a cohort of 7861 participants chosen to closely resemble the demographic characteristics of the US population, this cfDNA test showed a specificity of 89.6% for advanced colorectal neoplasia and an overall sensitivity of 83.1%. The false positive rate was 10.1%. This is within the acceptance criterion set by the FDA for other approved screening tests for colorectal cancer. The detection of advanced precancerous lesions however remains a challenge as the detection sensitivity for premalignant lesions was only 13.2%.

Colon Image by brgfx on Freepik.
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