The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is 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 to us by the authors. Use the ‘Next’ and ‘Previous’ buttons to navigate.
1Somatic mutant clones colonize the human esophagus with age
Why is this paper important?
“This and the next on the list are two papers that highlight the need to explore the role of mutations in cancer-associated genes in normal tissues.” Alberto Bardelli, EACR President
I. Martincorena, J.C. Fowler et al., Science volume 362, issue 6417, pages 911-917
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
2Age-related remodelling of oesophageal epithelia by mutated cancer drivers
A. Yokoyama, N. Kakiuchi, T. Yoshizato et al., Nature volume 565, pages 312–317 (2019)
Brief summary of the findings
Expansion of clones having mutations commonly seen in cancer has recently been reported in apparently normal tissues, such as blood and skin. However, it is poorly understood how those clones evolve from early infancy to the end of the life span in terms of their frequency and size and how its dynamics is affected by environmental/genetic factors to contribute to cancer.
In the current study, through unbiased sequencing of micro-scale esophageal samples, we show age-related, progressive expansion of driver-mutated clones in physiologically normal esophageal epithelia, which is substantially accelerated by alcohol drinking and smoking, well-known risks for esophageal cancer (ESCC). Driver-mutated clones emerge multifocally from early childhood, increase their number and size with aging, ultimately replacing almost entire esophageal epithelia in the extreme elderly. Despite a substantial overlap in mutated drivers, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in PNE, compared to ESCC, suggesting a discrete mechanism of positive selection. Mutations are typically acquired as the first hit before late adolescence, as early as early infancy, and significantly increase their numbers with smoking and drinking. Remodeling of esophageal epithelia is an inevitable consequence of normal aging, differentially impacting cancer development depending on lifestyle risks.
Future impacts of the findings
Our result suggests that positive selection of somatically mutated clones is pervasive and found in esophagus in every individual with ageing. However, despite a substantial overlap of driver mutations to those in cancer, these clones, even those carrying typical cancer derivers, such as TP53, rarely progress to cancer during a normal lifespan, suggesting the presence of a large barrier to carcinogenic transformation. Meanwhile, the pervasive and strong age-dependence nature of expansion suggest that such clonal expansion may play a role in tissue aging, which, together with difference from cancer, is an emerging issue to be intensively addressed in the future.
3Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids
K.K.Dijkstra, C.M.Cattaneo et al., Cell volume 174, issue 6, pages 1586-1598.e12
Brief summary of the findings
The success of immunotherapies aimed at reinvigorating tumor-reactive T cells has spread from melanoma to epithelial tumor types, including non-small cell lung cancer (NSCLC) and mismatch repair deficient colorectal cancer (dMMR CRC). However, clinical response varies between patients. Patient-specific model systems to study what determines sensitivity or resistance have been lacking due to the low efficiency of establishing tumor cultures.
Tumor organoid cultures are 3D cultures retaining morphological and genetic features of the original tumor. Importantly, they can be established with high success rate. We therefore evaluated whether tumor-reactive T cells can be generated from peripheral blood by co-culturing circulating lymphocytes with autologous tumor organoids. Using tumor organoids derived from NSCLC and dMMR CRC, in approximately ~50% of MHC-I+ samples, a population of tumor-reactive CD8+ T cells were induced after two weeks of co-culture. These T cells were largely specific for tumor antigens, as reactivity was also seen against single cell digest of the original tumor, but not against healthy colon or airway organoids from the same patient. In all four cases tested, induced T cells killed tumor organoids in an MHC-dependent manner.
Future impact of the findings
The co-culture system we describe represents a potential minimally invasive source of patient-specific tumor-reactive T cells that could be used for adoptive T cell transfer therapy, bypassing the need for samples derived from surgical resection.
Furthermore, the system allows the investigation of different aspects of the interaction between T cells and tumor cells. Mechanisms of resistance to T cell pressure can be dissected and studied at different time points during treatment, providing a means to test effective combinations of therapies at the level of the individual patient.
4A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
D.S. Thommen et al., Nature Medicine volume 24, pages 994–1004 (2018)
Summary
Evidence from murine chronic infection models suggests that the expression level of PD-1 can distinguish CD8+ T cell subsets that respond differently to PD-1 blockade. To assess whether similar T cell states exist in human cancer, we isolated and characterized three subpopulations of intratumoral T lymphocytes (TILs) with high, intermediate and negative PD-1 expression from non-small cell lung cancer specimens. We identified a transcriptionally distinct CD8+ T cell subset with bright PD-1 expression that was specific to the tumor (termed PD-1T TILs). Compared to T cells with intermediate or negative PD-1 expression, PD-1T TILs were highly proliferative and contained an enriched capacity for tumor recognition. While PD-1T TILs lost canonical T cell functions, they secreted the chemoattractant CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. The presence of a high number of PD-1T TILs in pretreatment biopsies was strongly predictive for response and survival following anti-PD-1 treatment in a small cohort of NSCLC patients.
Future impacts of the findings
The observation that PD-1T TILs are a highly proliferative subset and acquire CXCL13 secretion suggests that these cells are not ‘exhausted’ in the sense of complete loss of effector function, but rather display an altered functionality at the tumor site. Their intrinsically high capacity for tumor recognition indicates a crucial role for the anti-tumor immune response and makes them an attractive target for novel T cell directed therapies. The predominant localization of PD-1T TILs within tertiary lymphoid structures suggests a potential role of these structures for immunotherapy response. Finally, the striking correlation of PD-1T TILs present in the tumor with therapy response makes them a potential novel biomarker for PD-1/PD-L1 targeting therapies.
5Organoid Modeling of the Tumor Immune Microenvironment
J.T. Neal, X. Li et al., Cell volume 175, issue 7, pages 1972-1988.e16
Summary
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.
6Sensitive tumour detection and classification using plasma cell-free DNA methylomes
S.Y. Shen, R. Singhania, G. Fehringer, A. Chakravarthy et al., Nature volume 563, pages 579–583 (2018)
Summary
Most approaches to detect circulating tumour DNA (ctDNA) currently focus on cancer-associated somatic mutations. However, there is only a small number of recurrent mutations available which limit its sensitivity. In addition, somatic alterations alone cannot identify tissue-of-origin. Shen et al., provides a novel method to profile DNA methylation in plasma cfDNA termed cfMeDIP-seq (cell-free methylated DNA immunoprecipitation and high-throughput sequencing). This novel approach captures all methylated cfDNA then followed by sequencing. It has technical advantages by circumventing DNA degradation and reducing risk of false methylated signal, which is common in bisulfite conversion methods, while being cost efficient, as only methylated fragments are sequenced. It also has biological advantages, as it depends on DNA methylation profiles, which are tissue-specific and cancer-specific, and leverages thousands of recurrent DNA methylation changes that frequently occur in most cancer types. Shen et al., validated cfMeDIP-seq in a collection of plasma cfDNA from healthy donors and seven different cancer types (PDAC, AML, CRC, Renal, bladder, breast and Lung cancers). Using a machine learning-based approach, they were able to accurately classify multiple cancer types. Moreover, the classifier performed well in an independent validation set of healthy controls (AUROC: 0.969), Lung Cancer (AUROC: 0.971), AML (AUROC: 0.980), and PDAC (AUROC: 0.918).
Future impacts of the findings
Shen et al., reported a proof-of-concept study that genome-wide DNA methylation profiling of plasma cfDNA can be used for highly sensitive cancer detection and classification. Further independent validation is warranted to assess clinical validity of cfMeDIP-seq. If successful, this approach could be important in the liquid biopsy toolbox for cancer early detection, monitoring of treatment response and residual disease. Finally, since DNA methylation is tissue-specific, this approach could potentially have applications beyond oncology, to detect or monitor any disease associated with tissue damage and release of tissue-specific cfDNA into the circulation.
7Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens
Papers 7-9 are all connected
“These three papers identify a new vulnerability in human cancers based on a novel synthetic lethal interaction.” Alberto Bardelli, EACR President
F.M. Behan, F. Iorio, G. Picco et al., Nature (2019)
Brief summary of the findings
The histological and molecular heterogeneity of cancer has hampered identification of tumour cell vulnerabilities that could be exploited therapeutically. Lack of efficacy is a leading cause of the high attrition rate during cancer drug development, and fewer molecular entities to new targets are being developed. Unbiased strategies that effectively identify and prioritize candidate targets in tumours could expand the range of targets, improve success rates, and accelerate the development of new therapies. This manuscript describes Project Score, the genome-scale CRISPR–Cas9 screening of 324 human cancer cell lines from 30 cancer types to prioritise candidate cancer drug targets. The authors used a novel data-driven framework to systematically prioritize new targets that not only takes into consideration the CRISPR fitness data, but also integrates genomic data and the suitability of candidate targets for drug development. The study identified hundreds of priority targets, notably including a synthetic-lethal dependency on Werner syndrome helicase (WRN) in microsatellite unstable cancer cells from multiple tumour types. This study provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets, and suggests specific new candidate drug targets.
Future impacts of the findings
The principles described in this study can inform the early stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets. The prioritisation of candidate targets, and specifically Werner syndrome helicase in microsatellite unstable disease, could lead to new therapies for patients. Data and methods described in this study are components of the Cancer Dependency Map, an international effort to identify all vulnerabilities – so called dependencies – in all cancer cells. The Cancer Dependency Map aims to create a knowledge base to catalyse a new wave of more effective, less toxic precision cancer medicines.
We have also released a website with access to explore and download all data that was generated by this study: https://score.depmap.sanger.ac.uk
8WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers
Papers 7-9 are all connected
“These three papers identify a new vulnerability in human cancers based on a novel synthetic lethal interaction.” Alberto Bardelli, EACR President
E.M. Chan, T. Shibue et al., Nature (2019)
Brief summary of the findings
Defects in DNA mismatch repair promote a hypermutable state called microsatellite instability (MSI). MSI contributes to the pathogenesis of several malignancies, especially subsets of colon, stomach, ovary and uterus cancers, collectively accounting for as many as 500,000 new cancer diagnoses per year worldwide. We hypothesized that the impaired DNA repair and ensuing accumulation of genomic aberrations in MSI may create specific vulnerabilities in these tumors, especially in other proteins related to DNA repair and stability. Therefore, we systematically analyzed genome-wide loss-of-function screens using CRISPR-mediated gene knockout and RNAi-mediated gene silencing across hundreds of cancer cell lines to identify genes selectively essential for the survival and proliferation of MSI cancers. We found that the WRN helicase is essential for MSI cancer models but dispensable in cancers without MSI. Depletion of WRN causes DNA double-strand breaks, ultimately inducing cell death and cell cycle arrest selectively in MSI cancer models. Furthermore, we established that the helicase enzymatic function of WRN is specifically essential in MSI cancers. These observations uncover a synthetic lethal relationship between MSI and loss of WRN and nominate WRN as a promising therapeutic target in MSI cancers.
Future impacts of the findings
Many MSI cancers respond favorably to immune checkpoint blockade. However, there remains a clear need for new therapies due to both common intrinsic and acquired resistance to these immune agents as well as toxicity that limits the use of immunotherapy in many patients. By demonstrating that WRN is a synthetic lethal vulnerability in MSI cancers, essential in MSI cells but dispensable in non-MSI cells, this report suggests that WRN inhibition could both serve as a highly effective and well-tolerated therapy against MSI cancers. These results strongly support the development of new WRN inhibitors.
9Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells
Papers 7-9 are all connected
“These three papers identify a new vulnerability in human cancers based on a novel synthetic lethal interaction.” Alberto Bardelli, EACR President
S. Lieb, S. Blaha-Ostermann et al., eLife 2019;8:e43333
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in severe genome integrity defects. ATP-binding deficient variants of WRN fail to rescue the viability phenotype of WRN-depleted MSI-H cancer cells. Reconstitution and depletion studies indicate that WRN dependence is not attributable to acute loss of MMR gene function but might arise during sustained MMR-deficiency. Our study suggests that pharmacological inhibition of WRN helicase function represents an opportunity to develop a novel targeted therapy for MSI-H cancers.
10A defined commensal consortium elicits CD8 T cells and anti-cancer immunity
“This paper investigates the role of 11 microbial strains that populate tumors in mice and their effect on the immune system.” Yardena Samuels, EACR Board Member
T. Tanoue, S. Morita et al., Nature volume 565, pages 600–605 (2019)
The vastly diverse ecosystem of microorganisms colonizing the healthy human gut – known as the microbiota – affects many aspects of host physiology, including the immune system. As such, microbiota composition has been implicated in a wide variety of diseases including cancer, and has been causally linked to patient response to immune checkpoint inhibitor (ICI) therapies. Nevertheless, identifying effector species and their mechanisms of action has proven challenging, thus precluding clinical translation.
Here, we use a gnotobiotic pipeline to rationally select, isolate, and characterize a consortium of 11 bacterial strains from healthy human feces that can potently induce interferon-g (IFNg)-producing CD8 T cells, which are known to promote anti-cancer immunity and the clearance of intracellular pathogens. By inoculating fecal samples from different healthy donors into germ-free (GF) mice, we found that the extent of IFNg+ CD8 T cell induction varied substantially based on basal microbiota composition. We then performed a series of rigorous selection steps including secondary microbiota transplants, treatment with various antibiotics, and correlation analyses to narrow down candidate effector strains, ultimately identifying a group of 11 strains that together robustly induce IFNg+ CD8 T cells. This induction was observed both locally and systemically, and was dependent upon CD103+ dendritic cells and expression of major histocompatibility class Ia molecules. Colonization of both GF and specific pathogen-free mice with the 11 strains enhanced clearance of intracellular pathogen Listeria monocytogenes in a CD8 T cell-dependent manner. Similarly, colonization with the 11 strains augmented spontaneous anti-tumor immunity in mice engrafted with MC38 adenocarcinoma cells, and further enhanced the efficacy of ICIs like anti-PD-1 and anti-CTLA-4 in adenocarcinoma and melanoma models. The 11 strains are rare, low-abundance components of the microbiota that have an outsized effect on host immunity and their genomes do not contain major virulence factors, toxins, or multidrug resistance, making this bacterial cocktail a promising therapeutic candidate to treat a variety of cancers.
11Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity
K. Vriens, S. Christen et al., Nature volume 566, pages 403–406 (2019)
Short summary
Most tumors have an aberrantly activated lipid metabolism. However, only particular subsets of cancer cells are sensitive to approaches targeting lipid metabolism, particularly fatty acid desaturation. Yet, how cancers can evade drugs that inhibit fatty acid desaturation is unknown. The lab of Cellular Metabolism and Metabolic Regulation, led by Sarah-Maria Fendt (VIB-KU Leuven Center for Cancer Biology), discovered that many cancer cells can rely on an unexplored alternative metabolic pathway for fatty acid desaturation. Specifically, Kim Vriens and Stefan Christen identified various cancer cell lines, murine hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway, which results in drug resistance. This discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers. Exploring this discovery is expected to lead to the identification of novel drug targets and an increased understanding of fatty acid composition induced alterations in cellular signaling.
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Observant readers may notice that our ‘Top 10’ list has 11 entries. We shortlisted so many great papers over the last months that we couldn’t limit ourselves to 10!
