Cancer Biology

eLife assessment

Gain-of-function mutations and amplifications of PPM1D are found across several human cancers and are associated with advanced tumor stage, worse prognosis, and increased lymph node metastasis. Unfortunately, clinical translation has so far not been possible due to the lack of PPM1D inhibitors with favorable pharmacokinetic properties. This useful study leveraged CRISPR/Cas9 screening to identify that SOD1 inhibition is synthetic lethal with PPM1D mutation in leukemia, although the mechanistic analyses were incomplete.

eLife assessment

This study based on the use of Cancer Drug Resistance Accelerator (CDRA) chip is valuable as a platform technology to assess chemoresistance mechanisms. The strength is convincing from the technological point of view. However, the use of a single cell line model and the lack of mechanistic insights could be improved.

eLife assessment

The authors' finding that PARG hydrolase removal of polyADP-ribose (PAR) protein adducts generated in response to the presence of unligated Okazaki fragments is important for S-phase progression is potentially valuable, but the evidence is incomplete, and identification of relevant PARylated PARG substrates in S-phase is needed to understand the role of PARylation and dePARylation in S-phase progression. Their observation that human ovarian cancer cells with low levels of PARG are more sensitive to a PARG inhibitor, presumably due to the accumulation of high levels of protein PARylation, suggests that low PARG protein levels could serve as a criterion to select ovarian cancer patients for treatment with a PARG inhibitor drug.

eLife assessment

This important study delineates the molecular changes driving the progression from actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC). Using state-of-the-art single-cell RNA profiling of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, thus covering comprehensive clinical courses of cSCC, the authors provide an invaluable data resource. This study identified several previously unreported and interesting candidate genes involved in different stages of the malignant progression of skin neoplasias, which have been validated in situ, and partially in vitro. Although data analysis needs improvement and comparison to other published data sets to fully support the claims and conclusions, these findings substantially advance our understanding of the molecular changes leading to skin cancer.

eLife assessment

This study highlights new insights into the mechanism of pheochromocytoma pathogenesis that remains poorly understood. In the context of hereditary syndromes, such as multiple endocrine neoplasia 2 (MEN-2), where RET mutation is the major driver of thyroid, parathyroid, and adrenal pathologies, including pheochromocytoma, this mechanistic dissection of RET and TMEM127 is fundamentally sound. While the significance was deemed important, the strength of the evidence was found to be solid, although additional validation work would strengthen the findings.

eLife assessment

This study presents a valuable finding for the treatment of PCCs by sequencing 16 tumor specimens from five patients with pheochromocytomas by single-cell transcriptomics and proposing a new molecular classification criterion based on the sequencing results and characterization of tumor microenvironmental features. The evidence supporting the claims of the authors is solid, although the inclusion of more patient samples would strengthen the study's conclusions. The work will be of interest to clinicians or medical biologists working on rare pheochromocytomas (PCCs).

eLife assessment

This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. While of significant interest to those working on the immune biology of urothelial cancer and drug discovery, this work does not provide any mechanistic insights into the role of DUX4 and immune suppression and the assessment on clinical samples forms the discovery part of a biomarker program, requiring further cohorts for validation.

eLife assessment

This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. While of significant interest to those working on the immune biology of urothelial cancer and drug discovery, this work does not provide any mechanistic insights into the role of DUX4 and immune suppression and the assessment on clinical samples forms the discovery part of a biomarker program, requiring further cohorts for validation.

eLife assessment

The reviewers have found the work to be valuable to the field of immunotherapy in the treatment of cancer. The data supporting the role of PDLIM2 as a tumor suppressor, and more immediately, as a strategy to improve the efficacy of immunotherapy treatment, was viewed as compelling. However, the results are lacking a completed mechanism, which would substantially expand the impact of the work.

eLife assessment

This study describes a potential role for mechanical stimulation on non-small cell lung cancer (NSCLC) development. The findings are important and their observations are interesting, as models to study exercise in a mouse cancer setting would have practical implications beyond lung cancer, and biological roles of osteocytes in bone metastatic cancer is an area of great interest for potential therapy development. However, the methods and data interpretation are incomplete and the claims of osteocytes inducing tumor dormancy are overstated. The mechanism by which osteocytes affect tumor cells is not clear and the authors' theory on this remains unproven since much of the data are correlative rather than causative, and adequate controls, data quantification, and confirmation with secondary cell lines are often lacking.

eLife assessment

This important research uses complementary CRISPR screening strategies to reveal novel pathways that prevent T cells from killing tumor cells. The evidence presented to support the claims is solid, although some additional assays defining the features of these novel pathways and their clinical relevance are still required. Overall, this work will be of broad interest to immunologists, cancer biologists, and those interested in cell adhesion and cell-cell communication.

eLife assessment

This study of extrachromosomal DNA (ecDNA) aims to identify genes that distinguish ecDNA+ and ecDNA- tumors. This timely study is important in addressing the genes responding to the amplification of the ecDNA. The data presented are for the most part solid, there were concerns regarding the clarity in the description of the analysis methods and whether the evidence for specific genes required to maintain the ecDNA+ state was entirely conclusive.

eLife assessment

Zhao et al describe a novel function for RAPSYN in bcr-abl fusion associated leukemia. They show that RAPSYN stabilizes the oncogenic BCR-ABL fusion protein. Their findings are important and the strength of findings is convincing. The reviewers have made suggestions about further strengthening the rigor by use of more primary samples.

eLife assessment

This study provides insights into the early detection of malignancies with noninvasive methods by developing a framework, which assesses methylation, CNA, and other genomic features. They established a solid model in discriminating malignancies from healthy controls, as well as the ability to distinguish tumor of origin. This important study will demonstrate its practical impacts in the clinic and other researchers of the field.

eLife assessment

This study presents a valuable finding on the combination treatment of ONC201/TIC10 with everolimus for metastatic ER+ breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer.

eLife assessment

This study presents valuable findings on the symptoms and disease trajectories preceding a diagnosis of pancreatic cancer in Denmark. The evidence supporting the claims of the authors is solid, although an error analysis of the text mining evaluation results and a discussion on how the findings can be applied in practice would strengthen the study. The work will be of interest to public health researchers and clinicians working on pancreatic cancer.

eLife assessment

This important study uses mathematical modelling to demonstrate that conformational autoinhibition of the RAF kinase is an important feature of its paradoxical activation by pharmacological inhibitors. This part of the theoretical analysis is highly compelling but its extension to the investigation of how the binding of 14-3-3 adaptors additionally contributes to the paradoxical activation phenomenon is incomplete and would benefit from more rigorous experimental validation. With the experimental part addressing 14-3-3-dependent regulation strengthened or the 14-3-3 part completely removed, this paper would be of considerable interest to cell biologists and cancer biologists, ultimately paving the way for improved RAF therapeutics.

eLife assessment

TP73 is a member of the p53 family of tumor suppressors. The authors provide compelling evidence that a TAp73-alpha to TAp73-gamma switch could be a frequent phenomenon in human cancers and provide novel evidence that TAp73-gamma has oncogenic functions via Leptin. The authors provide a substantial amount of high-quality data and convincingly demonstrate a novel function of this specific isoform of p73 in lipid metabolism and tumorigenesis.

eLife assessment

Overall, this is an interesting topic of study, and the conclusions could be of relevance more broadly. However, mechanistic support, limited TTF frequencies/timing, and visual support of the quantitative data would be critical in order to provide convincing and rigorous support for this interesting concept.

eLife assessment

This work examines a role for altered splicing in pancreatic tumorigenesis by interrogating effects of a specific mutation in the Sf3b splicing factor in pancreatic organoid and cell line growth primarily, with some in vivo work also performed. There is significant potential in the study but there is a concern about the lack of in vivo validation of claims that are most relevant to metastatic progression and the focus on one specific mechanism at the expense of other possible effects on splicing of factors important for disease progression.