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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1Mitotic clustering of pulverized chromosomes from micronuclei
Lin, Y-F. et al. Nature. 618: 1041-1048 (2023).
doi: doi.org/10.1038/s41586-023-05974-0.
Summary of the findings
Cancer genomes commonly harbor complex rearrangements driven by chromothripsis, the catastrophic shattering and reassembly of individual chromosomes. Chromothripsis can be initiated by mitotic errors that entrap mis-segregated chromosomes within micronuclei, which are susceptible to DNA damage and replication defects that lead to chromosome shattering in the subsequent mitosis. Most of the chromosomal fragments are then reassembled in random order to generate rearrangements. However, since most fragments lack a centromere and cannot attach to spindle microtubules, how shattered chromosomes undergo segregation during mitosis and reincorporation into daughter cell genomes was unknown. Lin et al. report that shattered chromosomes cluster in spatial proximity during mitosis, which biases fragment distribution toward one daughter cell. The authors identify the CIP2A–TOPBP1 complex as the mitotic tether, the inactivation of which disperses fragments throughout the mitotic cytoplasm.
Since shattered chromosomes are mostly inherited by one daughter cell, these findings predict that some cancer genomes would exhibit complex rearrangements lacking changes in DNA copy-number. Indeed, such copy-number-neutral rearrangements, termed balanced chromothripsis, are found in ~5% of diverse tumors and underpin the acquisition of recurrent driver events, including fusion oncogenes. This work highlights a mechanism that drives specific patterns of genome rearrangements from an initial chromosome segregation error.
CIP2A-TOPBP1-mediated mitotic clustering of pulverized chromosomes from micronuclei facilitates balanced rearrangements in one of the daughter cells following mother cell division. In the absence of CIP2A-TOPBP1, pulverized fragments disperse throughout the mitotic cytoplasm and stochastically partition into both daughter cells. The figure and figure legend were taken from Extended Data Figure 11 from the original article (https://www.nature.com/articles/s41586-023-05974-0#Sec30) published Open Access under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Future impact
It remains unclear what are the precise DNA lesion(s) that recruit CIP2A and TOPBP1 to micronuclei during interphase and/or to shattered chromosomes in mitosis. Additionally, further mechanistic studies are needed to determine how this protein complex functions to tether chromosome fragments, whether other unidentified components are involved, and how these processes are regulated in diverse contexts. Lastly, further investigation is needed to define the impact of balanced chromothripsis on cancer genome evolution and tumorigenesis.
2Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding
Riera-Domingo, C. et al. Science Advances. 9(12): (2023).
doi: doi.org/10.1126/sciadv.add5028.
Summary of the findings
Metastasis remains the leading cause of death for cancer patients. To colonize distant organs, circulating cancer cells (CCCs) need to attach to and cross the endothelial barrier. The mechanisms controlling the homeostasis and activation of quiescent endothelial cells (ECs) in the pre-metastatic niche, key to preventing or granting access to CCCs, remain poorly defined. In their study, Riera-Domingo et al. have uncovered a novel angiocrine function of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5) in ECs, acting as physiologically relevant gatekeeper of the vascular barrier integrity. Co-expression of TRAIL and DR5 in adult quiescent ECs allows them to interact intracellularly with each other, resulting in the blockade (and not in the activation) of DR5 signaling and thereby safeguarding EC survival, promoting a resting antiadhesive state, and ultimately ensuring a tight and quiescent vascular barrier. In absence of endothelial TRAIL, DR5 signaling is unleashed, compromising the integrity of the vascular barrier, promoting inflammatory cell recruitment, and favoring metastatic cell adhesion and lodging. The protective function of endothelial TRAIL was counteracted both by tumor-derived signals, which silenced TRAIL, and by TRAIL decoy receptors (DcRs), which entrap and endogenously inhibit TRAIL. Excitingly, blocking TRAIL receptors or promoting the exogenous expression of TRAIL via TRAIL mRNA delivery by endothelium-targeting lipid nanoparticles conferred protection against metastasis in pre-clinical models of breast cancer.
High TRAIL expression in quiescent ECs of certain healthy adult organs (i.e., lung and liver) holds DR5 intracellularly and prevents its activation, thereby supporting cell survival, quiescence, and a resting anti-inflammatory/antiadhesive state. Together, this ensures the stability of the vascular barrier. During cancer progression, TRAIL transcriptional downregulation in response to systemic tumor-derived factors (i.e., VEGF-A, PlGF, and others) or DcR-mediated entrapment liberates DR5 and increases DR5 availability at the cell surface of ECs in distant organs, which is sufficient to trigger its activation in a ligand-independent manner. Consequently, EC apoptosis and NF-κB/p38–mediated EC inflammation compromises vascular integrity, favoring the subsequent leukocyte recruitment and ICAM1/E-Selectin–mediated cancer cell adhesion. Altogether, tampering with the angiocrine function of TRAIL in ECs in distant organs fosters the establishment of a PMN and, subsequently, cancer cell dissemination and metastasis. (This illustration was created with BioRender)
Future impact
Besides highlighting an important mechanism that functions as gatekeeper of the endothelial lining in a healthy organ, this study has important implications regarding the use of therapeutics exploiting the TRAIL pathway. It highlights a possible divergent effect of exogenous versus endogenous TRAIL and unveils a prometastatic role of DR5 in the stroma, raising the question of whether TRAIL receptor antagonists may be more suitable than TRAIL receptor agonists in certain patients. Moreover, it provides evidence that targeting TRAIL DcRs restrains metastasis, and provides proof-of-concept that reinforcing the expression of TRAIL specifically in ECs could have therapeutic benefits against metastasis.
3The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer
Mattox, A., K. et al. Cancer Discovery. 13: 2166–79 (2023).
doi: doi.org/10.1158/2159-8290.CD-21-1252 .
Summary of the findings
Studies over the past several decades have demonstrated that cell free DNA (cfDNA) concentrations from patients with cancer are often elevated above the levels of patients without cancer. However, the sources of this “extra” cfDNA have not been determined. To better define the source of this extra cfDNA, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary, as well as 64 patients without cancer. We found that leukocytes, not the primary tumor or surrounding normal epithelial cells from the cancer’s tissue of origin, contributed the majority of cfDNA in nearly all samples, regardless of total cfDNA concentration. These findings were also true in ostensibly healthy individuals that had high levels of cfDNA. These data suggest that cancers have a systemic effect on cell turnover or DNA clearance.
4Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation
Wischnewski, V. et al. Nature Cancer. 4: 908-924 (2023).
doi: doi.org/10.1038/s43018-023-00566-3.
Summary of the findings
The development of a proliferative, aggressive tumor within the brain generally reduces life expectancy to approximately one year following diagnosis. While a productive anti-tumor immune response would be required to effectively control or eliminate the cancer, brain-intrinsic mechanisms of immune-suppression can interfere with the response of tumoricidal immune cells – to protect the brain tissue from excessive neuroinflammation. Critically, how these mechanisms affect the abundance, phenotypes, and functions of brain tumor-infiltrating T cells is not yet well defined. To shed light on these processes, the authors deeply interrogated T cells in patients with different types of brain cancer, either intracranial or extracranial in origin, using a diverse panel of orthogonal analyses on single-cell, spatial, and bulk population levels. The study identified a subgroup of patients with brain metastases (BrM) that showed high accumulation of CXCL13-expressing CD39+ CD8+ potentially tumor-reactive T (pTRT) cells in their tumors. Notably, the high abundance of pTRT cells in this subset of lung-BrM samples was comparable to frequencies in primary non-small cell lung cancer, analyzed in parallel. By contrast, pTRT cells were infrequent in all other analyzed BrM tumors (including from primary breast and other lung cancer samples) and all gliomas. These low proportions of pTRT cells were similar to their analysis of primary breast cancers. These findings indicate that T cell-mediated tumor reactivity can occur within the brain, but only in a subgroup of patients.
Identifying differences in the abundance and phenotype of tumor-infiltrating T cells among patients with brain cancers of intracranial or extracranial origin. All gliomas and a subgroup of BrM samples showed low abundance of total T cells and pTRT cells, which is similar to the frequencies detected in primary (extracranial) breast cancer tissue. Another subgroup of BrM tumors were highly infiltrated with T cells, and particularly with pTRT cells, as well as type I-interferon stimulated macrophages, an immune cell composition similarly observed by the authors in primary lung tumors.
Future impact
This research provides a high-resolution analysis of T cells in patients with primary or metastatic brain cancer, an invaluable resource for the development of brain tumor-specific immunotherapies. In addition, the study highlights that patient stratification could be required for optimal treatment selection, particularly in the context of immunotherapy. BrM patients with high pTRT cell abundance may benefit from T cell-reactivation, while other subgroups would likely require strategies to additionally increase the frequencies of tumor-specific T cells. Thus, research into how to evaluate tumor-reactive T cell abundance in patients with a brain tumor in a non-invasive, or minimally invasive, manner is urgently required to achieve such patient stratification in the future.
5Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits
Sanchez-Aguilera, A., Masmudi-Martín, M. et al. Cancer Cell. 41 (9): 1637-1649.E11 (2023).
doi: doi.org/10.1016/j.ccell.2023.07.010.
Summary of the findings
Brain metastases represent a major source of morbidity in cancer patients, with dramatic effect in their quality of life. These people exhibit a cognitive impairment that have been traditionally thought to result from the mass effect of the tumor growth. In this paper, the authors challenge this view and show that different experimental models of brain metastasis co-opt the function of the nearby neuronal circuits in vivo in a very specific manner. They recorded the intracranial electrical activity surrounding different brain metastasis types from various primary sources and oncogenomic profiles, and found characteristic features in the local field potential (LFP). These alterations were associated to changes in the density of GABAergic inhibitory synapses, calcium activity and specific transcriptional programs. For instance, they identified deregulation of the transcription factor Egr1 with roles in synaptic plasticity and angiogenesis, as a potential link with changes in electrical activity. Using data science and machine learning strategies, the authors show that a model trained in LFP signatures surrounding the three different brain metastasis can help to disambiguate between subtypes when confronted with recordings from a different metastatic line, and to anticipate brain metastases early in advance.
Figure legend. Three brain metastatic cell lines were inoculated in the same area of the brain where they generated tumors of the same size : E0771-BrM, a breast cancer brain metastatic cell line (green); B16/F10-BrM, a melanoma brain metastatic cell line (red); and 482N1, a lung cancer brain metastatic cell line, (blue). Mice with brain metastases were evaluated with electrophysiology (local field potential, LFP) to determine the impact of the tumor on brain activity in vivo. The LFP profiles clearly reflected heterogeneity on the impact of each brain metastasis model on neural activity, being the 482N1 the model generating the highest impact on neuronal communication. The computational analysis of the electrophysiological profiles allowed identifying the Principal Components that defined the heterogeneity in the electrophysiological patterns. This information was further exploited with artificial intelligence (e.g., Decision Trees) to prove the value of brain activity as a biomarker to define whether in a brain there is a metastasis and even the subtype of metastases. In our ongoing search to define the underlying cellular and molecular causes of the differential impact on neural circuits independent on the tumor mass effect we have found that the 482N1 model specifically decrease peritumoral inhibitory synapses (iSinapsis) and calcium activity. In addition we identified 51 genes specifically upregulated in the 482N1 model, including the transcription factor Egr1. Ctx: cerebral cortex; Hippo: hippocampus; Met: metastasis.
Future impact
This work opens the field to investigate the functional fingerprints of the crosstalk between cancer cells and the surrounding neuronal circuit as a potential translational biomarker. The concepts and potential mechanisms that are shown in this work advocate for considering a systematic cognitive assessment and electroencephalographic characterization of patients with brain metastases to advance artificial intelligence application for improved diagnostic tools. In addition, the possibility that a molecular mechanism underlies the impact of brain metastases on neuronal communication also offers the opportunity to develop a new therapeutic strategy aimed to improve the quality of life of these patients.
6Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Goldman, O., Adler, N., L. et al. Cancer Discovery. 13 (7): 1616–1635. (2023).
doi: 10.1158/2159-8290.CD-22-1062.
Summary of the findings
The liver is a major metabolic and immunological organ that preserves systemic homeostasis under stress. Goldman, Adler, and colleagues describe the involvement of liver metabolism in extrahepatic tumor growth and progression. Following cancer-induced systemic inflammation, they find that innate immune cells are recruited to the liver by CCL2. The resulting interactions lead to activation of Erk, secretion of IL-6 from immune cells, and initiation of STAT3 signaling in hepatocytes. Consequently, there is an almost complete loss of HNF4α, the master regulator of liver metabolism. Loss of HNF4α perturbs the function of central liver metabolic pathways such as the urea cycle, albumin, and fatty acid synthesis, increasing plasma availability of nitrogen-rich metabolites such as ammonia, glutamate, and aspartate, promoting tumor growth. Notably, the high ammonia levels inhibit lymphocyte proliferation and activation, further empowering cancer cells’ survival. In addition, the dysregulation of albumin and fatty acid synthesis likely contributes to cancer progression to systemic manifestations such as weight loss. Indeed, maintaining HNF4α using a viral vector preserves liver metabolism, alleviates fat and muscle loss and weight loss, and increases survival in a pancreatic cancer mouse model. Significantly, scoring the biochemical liver profile in breast and pancreatic cancer patients can predict weight loss.
Future impact
Cancer-associated cachexia manifestations such as weight loss do not efficiently respond to therapy or a high-calorie diet. The findings described here have impactful clinical implications, as they offer an opportunity for early intervention by providing a liver biochemical score that identifies patients at risk for weight loss in breast and pancreatic cancer patients on the day of diagnosis. Additionally, the findings demonstrate that maintaining liver expression of HNF4α, preserves liver metabolism and can effectively alleviate weight loss in cancer mouse models. Notably, the results highlight the importance of understanding the tumor MACRO-environment for benefiting cancer diagnosis and therapy.
7Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax.
Waclawiczek, A., Leppä, A.-M., Renders S. et al. Cancer Discovery. 13:1408–27. (2023).
doi: 10.1158/2159-8290.CD-22-0939.
Summary of the findings
Treatment with BCL-2 inhibitor Venetoclax (VEN) and Hypomethylating agents (HMA) has transformed therapies for elderly AML patients and relapsed/refractory disease. While mutational profiling enriches for good and poor response, no personalized biomarker predicting HMA/VEN response exists to date. Waclawiczek et al., show that GPR56+ Leukemic stem cells (LSCs) but not bulk AML cells predicts response to HMA/VEN in vitro. We then examined intracellular expression level of the three BCL2-family members, BCL-2, BCL-xL and MCL-1 within LSCs in >70 HMA/VEN treated patients by flow cytometry. This revealed that high BCL-2 expression in LSCs with concomitant low expression of BCL-xL or MCL-1 predicted good response to HMA/VEN. In contrast, low BCL-2 and high BCL-xL/MCL-1 expression in LSCs was strongly associated with poor response. Using these insights, we combined the intracellular expression level of these three BCL-2-family members into a MAC-Score. Applying MAC-scoring in LSCs, but not bulk AML cells, provided a clear distinction between patients responding or failing HMA/VEN therapy and was associated to time to relapse. MAC-Scoring also predicted HMA/VEN response in a salvage setting and its predictive power of 97% outperformed genetic markers. MAC-scoring is fast and affordable and thus qualifies as a personalized predictive biomarker to guide AML therapy.
The graphical illustration was taken from Figure 5K from the original article (https://aacrjournals.org/cancerdiscovery/article/13/6/1408/726964/Combinatorial-BCL2-Family-Expression-in-Acute), published as an open access article and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license (https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en). The graphical illustration was created using a BioRender.com license.
Future impact
Currently MAC-scoring is being integrated into the clinical flow cytometry pipelines to validate this technology prospectively and in real life conditions. Following validation MAC-Scoring allows biomarker based clinical trials to deescalate induction therapy for younger, fit AML patients. In the future, information on BCL-xL and MCL-1 gathered through MAC-Scoring can guide patient selection for clinical trials with new BCL-xL or MCL-1 inhibitors or combinatorial approaches in a front line or relapsed refractory setting. MAC-scoring is not limited to AML but could also be adapted and applied to other diseases sensible to proapoptotic therapy such as CLL or lymphoma.
8Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation
Gaffen, Y., Anand, S., Akiyama Y. et al. Cell. 186 (18):3945-3967.E26. (2023).
doi: 10.1016/j.cell.2023.07.013.
Summary of the findings
Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.
**The summary and graphical abstract were taken from the original article (https://doi.org/10.1016/j.cell.2023.07.013) published Open Access under a Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) License (https://creativecommons.org/licenses/by-nc-nd/4.0/).**
9VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry
Delgado-Bellido, D., Zamudio-Martínez, E. et al. Cell Death & Disease. 14:135. (2023).
doi: 10.1038/s41419-023-05666-7.
Summary, future impact and graphical abstract by Alexandra Boitor, EACR Scientific Officer
Summary of the findings
Vasculogenic mimicry, or the ability of aggressive cancer cells to form a blood network independently from endothelial cells, is associated with highly invasive tumours and treatment failure. In this paper, Delgado-Bellido et al. are building on previous research from F. J. Oliver’s laboratory on VE-cadherin involvement in the FAK pathway in melanoma. The authors unveil a role for Y658 phosphorylated VE-cadherin in the process of vasculogenic mimicry at an epigenetic level, by enhancing the activity of the TCF-4 transcriptional factor by the FAK-dependent formation of a VE-Cadherin/β-catenin/TCF-4 complex.
Future impact
Results from this study hold the promise of improving current treatments for melanoma. The authors suggest that a new treatment approach that combines FAK inhibitors with anti-angiogenic treatments could reduce tumour growth.
10MYC determines lineage commitment in KRAS-driven primary liver cancer development
D’Artista, L. et al. Journal of Hepatology. 79(1):141-149 (2023).
doi: 10.1016/j.jhep.2023.02.039.
Summary, future impact and graphical abstract by Alexandra Boitor, EACR Scientific Officer
Summary of the findings
In this paper, D’Artista et al are investigating both the “cell of origin” and the molecular mechanisms that govern the development of primary tumours in the liver. Building upon previous work demonstrating that hepatocytes pose increased plasticity, the authors implicate MYC as a master regulator in lineage commitment in primary liver cancer. More exactly, the authors of this paper suggest that high MYC levels and MYC controlled transcriptional activity of FOXA1, FOXA2 and ETS1 can determine the commitment of malignant hepatocytes towards hepatocellular carcinoma. The overexpression of Ets1 together with shRNA targeting Foxa1 and Foxa2 in MYC transformed hepatocytes caused a switch from hepatocellular carcinoma to intrahepatic cholangiocarcinoma development (as shown in the Figure).
Future impact
The authors highlight the relevance of their findings for regenerative medicine and modulation of cancer response to treatment.
