Highlights in Cancer Research: December 2024

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. Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list. Coagulation factor X promotes resistance to androgen-deprivation therapy in prostate cancer Calì , B. et al. Cancer Cell. 42 (10): 1676-1692.e11. (2024). doi: 10.1016/j.ccell.2024.08.018. Summary of the findings Despite the latest advancements in the treatment options for prostate cancer (PCa), many patients develop metastatic castration-resistant prostate cancer (mCRPC), characterized by elevated counts of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Single-cell RNA sequencing of the tumor microenvironment (TME) of multiple castration-resistant prostate tumor models has revealed that PMN-MDSCs serve as a significant extra-hepatic source of coagulation factor X (FX). Interestingly, FX activation occurs only within the prostate TME and requires Tissue Factor (TF). . Active FX (FXa) promotes androgen-independent tumor growth by activating protease-activated receptor 2 (PAR2) and inducing ERK1/2 phosphorylation in tumor cells, both in vitro and in vivo. Conversely, inhibition of FX activity—whether genetically or pharmacologically—reduced the oncogenic effects of PMN-MDSCs, slowed tumor progression, and enhanced the efficacy of enzalutamide in multiple mouse models. Intriguingly, PMN-MDSCs expressing high FX levels also expressed the surface marker CD84 and showed reduced CXCR2 levels, suggesting an aggressive subset of PMN-MDSCs with decreased sensitivity to CXCR2 inhibitors. . Clinically, high plasma levels of FX and a specific gene signature associated with FX and CD84 expression in PMN-MDSCs in tumor samples correlate with poorer survival outcomes in PCa patients. Further, immunostaining of human prostate tissue microarrays revealed that PAR2 expression increased with tumor progression, being significantly higher in CRPC compared to hormone-sensitive tumors and benign prostate hyperplasia. Of note, prostate tumors lacking PAR2 were associated with markedly longer disease-free survival in patients with prostate adenocarcinoma. . Future impact Several evidence have demonstrated a tight association between hypercoagulability and cancer, highlighting a role for EMT and metastasis formation. The discovery that a coagulation factor can directly support tumor growth and resistance to therapy, independently from the coagulation cascade, underscores the potential for developing new treatment strategies targeting intratumor coagulation factors in prostate cancer. Also, the identification of a gene signature associated with poorer survival, as well as the discovery that elevated plasma levels of FX and high PAR2 tumor expression associate with shorter survival, unveiled a new prognostic role for FX-PAR2 axis in CRPC patients. . Read more in Cancer Cell Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis Padmanaban, V. et al. Nature. 633: 207–215 (2024). doi: 10.1038/s41586-024-07767-5. Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer Summary of the findings It has been known for decades that tumours are innervated by the peripheral nervous system. Whilst this is a growing field of research, and more and more aspects of cancer neurobiology are being described in the literature, there are still caveats in our knowledge. One such poorly understood aspect is the role that sensory innervation plays in breast cancer metastasis. . . The authors of this paper build on their previous work that identified overexpression of the axon-guidance protein SLIT2 in the endothelium of metastatic breast tumours as a driver of metastasis. In this paper, Padmanaban et al., show that SLIT 2 drives breast tumour innervation, and that increased sensory innervation in tumours drives cell proliferation and metastasis in breast cancer. In this study, the pro-metastatic effects were driven by neuronal SP secretion in the tumour microenvironment. The authors propose a model through which SP induces apoptosis in a subpopulation of cancer cells that express TACR1, leading to ssRNA release in the tumour microenvironment. The ssRNA released interacts with TLR7 on the surface of remaining tumour cells and mediates the pro-proliferative and pro-invasive behaviour in an immune-independent fashion, likely activating non-canonical PI3K signalling downstream of TLR. The authors also provide a proof-of-concept for therapeutic targeting: aprepitant, a drug used to treat nausea that acts as an antagonist of TACR1, showed the ability to inhibit tumour growth and metastatic progression in cell culture and PDX models. . . . Read more in Nature Targeting cancer with small-molecule pan-KRAS degraders Popow, J., Farnaby, W., Gollner, A., Kofink, C. et al. Science. 385 (6715): 1338-1347 (2024). doi: 10.1126/science.adm8684. Summary of the findings More than 40 years after the identification of RAS as bona fide oncogenes, only one allele of one isoform, the Glycine to Cysteine mutation of KRAS, has been successfully drugged to date. Here we describe a biophysics and structure guided approach towards the discovery of ACBI3, a small molecule that can potently degrade wildtype KRAS as well as 13 out of the 17 most prevalent oncogenic KRAS alleles, including the most prevalent alleles, G12D and G12V. We demonstrate both rapid and potent cellular degradation is coupled with more profound and sustained pathway modulation as compared with inhibition. We support a detailed understanding of how a series of prototype bifunctional degraders induce de novo ternary complexes between KRAS and the E3 ligase recognition sub-unit von Hippel-Lindau protein (VHL) with both high-resolution X-ray co-crystal and cryo-EM ternary structures, which guided our compound optimisation. Subsequently, we demonstrate that degradation of oncogenic KRAS leads to tumour regression in vivo in both G12D and G12V models. . . [caption id="attachment_9155" align="alignnone" width="752"] (A) Degradation of retrovirally transduced HiBiT-tagged indicated KRAS mutants by ACBI3 in GP5d cells (18 hours, n = 3 biological replicates). (B) and (C) Ternary structure based design of ACBI3 (D) Whole cell proteomics MS analysis of GP2d cells treated with 50 nM ACBI3 or inactive stereoisomer compound 8 (8 hours, N=3). HRAS (log2 fold change -0.0006, -log P 0.001) and NRAS (log2 fold change -0.12, -log P 0.52) levels were not significantly affected.[/caption] Future impact These findings support that a single targeted protein degrader molecule may be capable of addressing a major proportion of KRAS driven cancers. . Read more in Science Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection Mazzone, P.J. et al. Cancer Discovery. 14 (11): 2224–2242 (2024). doi: 10.1158/2159-8290.CD-24-0519. Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer Summary of the findings Lung cancer is one of the leading causes of death for both men and women in the US, in part due to late diagnosis. Screening programmes based on chest low-dose computed tomography (LDCT) are in place, but the uptake by the public is low. This is in part due to limited access, concerns for radiation toxicity associated with repetitive CT imaging, limited availability of specialist follow-up and same-day point-of-care scheduling leading to increased anxiety following the detection of lung abnormalities. The introduction of a blood test as a pre- LDCT screening evaluation tool has the potential to expand lung-cancer screening. . The blood test was trailed on 958 individuals from 47 centres across 23 states in the United States, 576 samples being used for training the algorithm and 382 for validation. The proposed approach is based on the DELFI (DNA Evaluation of Fragments for Early Interception). Low coverage (∼3×) whole-genome sequencing was performed on 504 nonoverlapping 5 MB regions, spanning 2.5 GB of the genome and comprising ∼80,000 fragments each. Fragmentation profiles from lung cancer patients displayed extensive genome-wide variation and comprised of a mixture of cfDNA profiles from peripheral blood as well as from the tumours. . During clinical validation and following normalisation of the test results to the population normally eligible for screening, the test showed an overall sensitivity of 80%. Sensitivity increased with cancer stage from 71% for Stage I cancer to, 89% and 88% for stages II and III and 98% for stage IV. The overall specificity was of 58%. This proportion of false positives is considered acceptable by the authors given that the blood test is designed as a pre-screening evaluation tool and all positive results would be followed with LDCT screening. . . Future impact “Lung cancer screening has poor adoption. Our study describes the development and validation of a novel blood-based lung cancer screening test utilizing a highly affordable, low-coverage genome-wide sequencing platform to analyze cell-free DNA fragmentation patterns. The test could improve lung cancer screening rates leading to substantial public health benefits.” . Read more in Cancer Discovery Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer Wang, X., Fang, Y., Liang, W. et al. Cancer Cell. 42 (10): 1729-1746.e8 (2024). doi: 10.1016/j.ccell.2024.08.019. Summary of the findings Immune checkpoint blockade (ICB) therapy is one of the most promising strategies for treatment of cancer. However, 85% of patients with CRC are microsatellite stable (MSS) and are ineligible to ICB therapy due to poor responsiveness. Here, Wang et al. report that CRC-promoting gut pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-programmed death-1 (PD-1) therapy. Fecal microbiota transplantation from MSS CRC patients with Fn-high abundance to germ-free MSS CRC mice conferred sensitivity to anti-PD-1 treatment compared to those receiving transplants from Fn-low counterparts. Consistent with this, Fn gavage in humanized, germ-free mice similarly boosted anti-PD1 efficacy against MSS CRC tumors. . This study further identified that Fn mediates anti-PD-1 promoting effect through its secreted metabolite butyric acid. Butyric acid acts as histone deacetylase (HDAC) inhibitor, suppressing HDAC3/8 activities in intratumoral CD8+ T cells, leading to the acetylation of histone H3 on lysine 27 at Tbx21 promoter region and subsequent over-expression of TBX21 protein. TBX21 in turn represses PD-1 expression, alleviating CD8+ T cell exhaustion and promoting the production of tumor killing cytokines. In patients with MSS CRC, high intratumoral Fn predicts a favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker for immunotherapy response in MSS CRC. . . [caption id="attachment_9157" align="alignnone" width="696"] Fusobacterium nucleatum sensitizes microsatellite stable colorectal cancer to anti-programmed death-1 therapy[/caption] Future impact MSS CRC is resistant to anti-PD-1 therapy. The findings by Wang et al. have translational relevance for novel strategy to boost anti-PD1 therapy in MSS CRC. By showing that high Fn abundance potentiates anti-PD-1 efficacy, this work implies that Fn abundance may be a potential biomarker for predicting responses to anti-PD-1 therapy in MSS CRC, which could help stratify patients who are likely to respond. Additionally, the identification of butyric acid as a key metabolite that activates intratumoral CD8+ T cells infers that increasing colonic butyric acid production could be a strategy to improve response to anti-PD-1 therapy in MSS CRC. . Read more in Cancer Cell Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations Youssef, K.K. et al. Nature Cancer. 5: 1660–1680 (2024). doi: 10.1038/s43018-024-00839-5. Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer Summary of the findings Epithelial plasticity is known to play a crucial role in cancer progression, but it is also involved in other pathological processes, such as fibrosis and in physiological processes, such as embryonic cell migration and tissue repair. In all these contexts, epithelial plasticity is triggered by epithelial to mesenchymal transition (EMT). In this paper, Youssef et al. investigate EMT in pathological and physiological models and defined two different EMT programmes: an embryonic-like EMT programme and an adult-like EMT programme consistent with wound healing behaviour. . Youssef et al. confirm through their experiments that SNAIL1 pioneers EMT induction, being involved in the activation of early mesenchymal genes, and the recruitment of other transcription factors required for EMT progression enhancing the regulation of various epithelial and mesenchymal markers. The authors show that following SNAIL1 activation, PRRX1 is needed for cells to progress from partial EMT to an invasive phenotype through focal adhesion kinase (FAK) signalling (embryonic-like EMT). Following SNAIL1 activation and in the absence of PRRX1 signalling, cells seem to activate a stable, partial EMT with residual cell-cell junctions characterised by dedifferentiation, inflammation and failure to invade (adult-like EMT; wound healing behaviour). Further experiments confirmed that both EMT programmes are hijacked during tumour progression: cells exhibiting characteristics of both EMT programmes can be found within the same tumour (breast cancer) with the inflammatory (partial) EMT cells distributed through the tumour and the invasive EMT cells localised towards the edges of the tumour. . . . Read more in Nature Cancer ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer Pozzato, C. et al. EMBO Molecular Medicine. 16 (10): 2402 – 2426 (2024). doi: 10.1038/s44321-024-00138-7. Summary of the findings Lung cancer, particularly non-small cell lung cancer (NSCLC), is one of the leading causes of cancer deaths globally. Around 30% of NSCLC cases involve mutations in a gene called KRAS, which drives aggressive tumor growth and often leads to resistance against standard treatments. While new therapies targeting proteins like FAK (Focal Adhesion Kinase) show promise, many tumors develop resistance, limiting their effectiveness. . In this paper, Pozzato et al. investigated the mechanisms underlying FAK inhibitor resistance in NSCLC. By examining the contribution of the different regulatory phosphorylation sites on FAK they discovered that ERK5 and CDK5, two enzymes, play crucial roles in maintaining the tumor-promoting functions of FAK. Inhibition of ERK5 and CDK5 together was found to significantly reduce cancer cell growth and induce cell death by increasing oxidative stress and triggering DNA damage. . Prolonged FAK inhibitor treatment in NSCLC cells induces resistance via ERK5 upregulation, which sustains FAK signaling and promotes cell survival. Inhibiting ERK5 restores drug sensitivity, causing DNA damage and cancer cell death. . The findings suggest that targeting ERK5 alongside FAK may offer a promising strategy to combat drug resistance and enhance the efficacy of NSCLC therapies in patients with KRAS mutations. . . [caption id="attachment_9160" align="alignnone" width="500"] Mechanism of FAK inhibitor resistance in NSCLC. (A) CDK5 and ERK5 positively regulate FAK activation. Combined inhibition of CDK5 and ERK5 (with the pharmacological inhibitors Seliciclib and XMD8-92 respectively), suppresses FAK function and triggers cancer cell death. (B) Prolonged treatment of cancer cells with FAK inhibitors triggers a drug tolerant cancer cell state, epithelial to mesenchymal transition (EMT) and upregulation of ERK5-mediated phosphorylation of FAK (at Ser910). Combined inhibition of FAK and ERK5 reverts the resistance and triggers cells death in vitro and in vivo.[/caption] Future impact This study suggests that dual inhibition of ERK5 and FAK could become a transformative approach in treating KRAS-driven NSCLC by significantly enhancing the effectiveness of FAK inhibitors and reducing drug resistance, which is a common challenge in targeted cancer therapies. The findings could pave the way for combination therapies that may extend patient survival and improve quality of life. Future clinical trials could explore ERK5 inhibitors, which are not yet widely available, as potential partners in combination therapies for lung cancer and possibly other cancers where similar resistance mechanisms are at play. . Read more in EMBO Molecular Medicine Macrophage-mediated myelin recycling fuels brain cancer malignancy Kloosterman, D.J., Erbani, J. et al. Cell. 187 (19): 5336-5356.e30 (2024). doi: 10.1016/j.cell.2024.07.030. Summary of the findings Glioblastoma is the most common and aggressive form of primary brain cancer. Despite significant advances in our understanding of this disease, the standard of care has remained unchanged. The lack of efficacy of novel therapies in glioblastoma, such as immunotherapies, is partly attributed to the accumulation of immunosuppressive, tumor-associated macrophages (TAMs) within the tumor microenvironment. However, the high macrophage heterogeneity displayed in glioblastoma challenges a “one-size-fits-all” therapeutic approach, calling for an in-depth appreciation of their immense plasticity. . In this study, we employ a multi-omics approach to resolve the heterogeneity and spatial diversity of TAMs, revealing a subset of pro-tumorigenic macrophages characterized by accumulation of lipids droplets. Mechanistically, cholesterol-rich myelin debris engulfment by TAMs drives the formation of lipid-laden macrophages (LLMs) which display immunosuppressive features. Importantly, LLMs are enriched in the most aggressive, mesenchymal subtype of glioblastoma. Mesenchymal cancer cells prime the formation of LLMs and co-localize with these cells to scavenge the myelin-derived lipids effluxed by LLMs to fuel cancer outgrowth. This study highlights how brain tumors co-opt the homeostatic, myelin recycling functions of macrophages to support malignancy. Altogether, we shed light onto the regulation of macrophage heterogeneity and advance potential new avenues for subset-specific targeting of macrophages in glioblastoma. . . [caption id="attachment_9161" align="alignnone" width="500"] Following engulfment of cholesterol-rich myelin debris through the lipid receptor CD36, tumor-associated macrophages acquire a lipid-laden phenotype in the glioblastoma tumor microenvironment. Lipid accumulation leads to Dhcr24 and lipid biosynthesis downregulation in lipid-laden macrophages (LLMs), which results in the accumulation of desmosterol. Following desmosterol-mediated LXR activation, LLMs downregulate inflammatory responses and upregulate the lipid exporters ABCA1/ABCG1 to promote cholesterol efflux. Mesenchymal (MES)-like glioblastoma cells scavenge LLM-derived lipids to fuel proliferation and fitness. Moreover, macrophage-mediated myelin uptake protects glioblastoma cancer cells from the myelin lipotoxic effect, altogether promoting glioblastoma malignancy.[/caption] Future impact This study identifies a novel mechanism through which immunosuppressive, lipid-laden macrophages are generated and fuel glioblastoma cell growth through transfer of myelin-derived cholesterol. The discovery of LLMs and the pro-tumorigenic functions they exert in the glioblastoma TME highlights the currently understudied aspects of metabolic rewiring as a central co-evolution feature in brain cancers, opening novel avenues for therapeutic interventions in this disease. Additionally, LLMs could represent novel biomarkers able to predict glioblastoma subtype composition, prognosis and response to immunotherapy. . Read more in Cell Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers Sundaram, L., Kumar, A., Zatzman, M. et al. Science. 385 (6713): eadk9217 (2024). doi: 10.1126/science.adk9217. Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer Summary of the findings One of the challenges in cancer research is identifying and understanding the diverse molecular features associated with different genetic lesions and gene regulatory changes that drive carcinogenesis and cancer progression. The Cancer Genome Atlas (TCGA) was created to map diverse molecular features associated with malignancy. One method employed to answer this question has been chromatin accessibility mapping using ATAC-seq, which led to the identification of several malignant signatures across 23 primary human cancer types. However, most studies were performed in bulk cancer tissues, so the current landscape of regulatory elements contains information from tumour-associated stromal or immune cells. In this paper, the authors aimed to deconvolute the existent data from TCGA for eight cancer types (74 individual samples) by employing single-cell chromatin accessibility. . The authors managed to successfully separate cancer cells, tumour-infiltrating immune cells and stromal cells based on the single-cell chromatin availability data. Furthermore, the authors were able to identify and measure chromatin accessibility differences in immune cell subsets from various cancer types, cis-regulatory differences between distinct subclones in two samples of glioblastoma and identify the most likely cell type of origin for several breast cancer subtypes. The authors also generated neural network models to predict the impact of genetic variation on chromatin accessibility. . . Read more in Science Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy Dias, M. H. et al. Cancer Discovery. 14 (7): 1276–1301 (2024). doi: 10.1158/2159-8290.CD-23-0216. Summary of the findings This study presents a novel and counterintuitive cancer therapy approach that paradoxically activates oncogenic pathways, exploiting cancer cells' reliance on stress response mechanisms for survival. Using colorectal cancer models, the researchers demonstrated that inhibiting Protein Phosphatase 2A (PP2A) with the drug LB-100 overactivates multiple oncogenic pathways in cancer cells. While these pathways typically drive cancer growth, their overactivation causes significant cellular stress, pushing the cells toward a breaking point. The addition of a WEE1 inhibitor further disrupted the cells' ability to manage this stress by impairing DNA damage repair and cell cycle checkpoints, leading to catastrophic mitotic failure and eventual cell death. . Notably, the combination of LB-100 and the WEE1 inhibitor was highly effective across various cancer models, including patient-derived tumors, highlighting its broad applicability. Additionally, cancer cells that developed resistance to the treatment lost their ability to form tumors, suggesting a significant reduction in their malignancy. These results underscore the potential of targeting cancer cells' inherent vulnerabilities through stress-induced lethality. By combining two agents to target the very nature of cancer cells, this strategy offers a promising alternative for combating drug-resistant cancers with potential applications beyond colorectal cancer. It also addresses a critical need for therapies that prevent recurrence and tumor progression. . . [caption id="attachment_9162" align="alignnone" width="400"] In the absence of treatment, cancer cells exhibit a balance between the levels of mitogenic signaling and cellular stress. The "paradoxical" hyperactivation of oncogenic signaling pathways overloads stress levels, while the WEE1 inhibitor adavosertib prevents these cells from mitigating and correcting the DNA damage stress, driving them to cell death.[/caption] Future impact This research introduces a fundamentally different approach to cancer treatment by exploiting core vulnerabilities of cancer cells through paradoxical activation of oncogenic pathways. The combination described in the manuscript and others based on the same rationale may be a powerful strategy to target drug-resistant and aggressive cancers, with potential applications across various tumor types. The findings could inspire the development of novel combination therapies that use cancer cells' "powers" against them. This approach may significantly improve outcomes for patients with advanced cancers, paving the way for more effective and durable therapeutic options in oncology. . Read more in Cancer Discovery

Highlights in Cancer Research: December 2024

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Highlights in Cancer Research: December 2024

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