Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Characterisation of ferroptosis response in small cell lung cancer neuroendocrine subtypes

Small cell lung cancer (SCLC) treatment has remained a major clinical challenge with very few newly approved treatment strategies in the last 30 years. After initial chemotherapy response SCLC almost invariably relapses presenting with intratumoural neuroendocrine (NE) subtype heterogeneity as a result of different cells-of-origin and subtype plasticity. SCLC is defined by loss of function mutations in tumour suppressor genes TP53 and RB1 as well as a significant tumour mutational burden (TMB), suggesting selective pressure to inactivate cell death pathways prior to therapy. However, a comprehensive analysis of cell death pathway availability in SCLC has not been pursued yet. In this study, through systematic characterisation of regulated cell death pathway availability in RNA-sequencing data of human treatment-naïve SCLC patient tissue, we find broad inactivation of the extrinsic apoptosis and necroptosis pathway components and high expression of genes preventing from ferroptosis. Ferroptosis is a recently described form of regulated cell death induced by iron-dependent accumulation of fatal lipid-peroxides resulting in destabilisation of the lipid bilayer and membrane rupture. In this study, we identified that non-NE mouse and human SCLC cells marked by low Achaete-Scute Homolog 1 (ASCL1) expression are uniquely primed for ferroptosis, while NE SCLC cells instead are highly vulnerable to thioredoxin (TRX) pathway inhibition. Non-NE SCLC presents with an elevated oxygenated lipidome and is selectively vulnerable to genetic or pharmacological induction of ferroptosis. We identified NE-differentiation marked by the NE lineage-defining transcription factor ASCL1 expression to determine ferroptosis resistance. ASCL1 suppresses glutathione synthesis in the NE SCLC subtype which acquires addiction to the thioredoxin (TRX) anti-oxidant pathway. Co-cultures replicating non-NE/NE intratumoural heterogeneity selectively deplete non-NE populations upon ferroptosis induction, while only TRX pathway inhibition eliminates NE cell populations. Importantly, single redox-pathway targeting induces NE/non-NE plasticity enabling treatment escape in SCLC. Hence, combined ferroptosis induction and inhibition of the TRX pathway kills established non-NE and NE tumours in xenografts, genetically engineered mouse models of SCLC and patient-derived treatment-naïve and refractory NE SCLC models. In SCLC but not lung adenocarcinoma, combined low expression of GPX4 and TRX reductase 1 (TXNRD1) identified a patient subset with significantly improved overall survival. Taken together, these findings reveal that informed cell death pathway mining in treatment-naïve SCLC can identify rational combination therapies which address SCLC NE/non-NE heterogeneity and plasticity under treatment

Non-neuroendocrine differentiation generates a ferroptosis-prone lipidome in small cell lung cancer (SCLC)

Our recent study revealed that non-neuroendocrine small cell lung cancer (SCLC) is sensitive to the induction of ferroptosis due to upregulation of ether lipid synthesis. While neuroendocrine SCLC is ferroptosis resistant, it acquires addiction to the thioredoxin pathway. Combined redox pathway targeting therefore achieves efficient anti-tumor activity in heterogenous SCLC

Ferroptosis in Cancer Cell Biology

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer

Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation

Oncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular reactive oxygen species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of ferroptosis in pancreatic organoids derived from the LsL-KRAS(G12D) expressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers

Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes

Loss of TP53 and RB1 in treatment-naive small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naive SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naive SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC. The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity