Cancer Biology

eLife assessment

This important and comprehensive study describes the development of a heterobifunctional degrader, which is used to provide insights into the mechanism of TEAD proteolysis, with potential implications for signaling pathways in cancer. While the methods are solid, the analyses and descriptions are still incomplete. With further molecular refinements, experimental controls, and a more cohesive and unified story, this article will be of interest to cancer biologists and scientists interested in proteostasis, cellular signaling, and post-translation modification of proteins.

eLife assessment

This study delves into the complex role of STAT3 signaling and its interplay with TGF-beta and SMAD4 in KRAS mutant pancreatic cancer. The authors demonstrate that both the presence and absence of STAT3, relative to SMAD4, can lead to poor PDAC differentiation and that STAT3 mutations affect p53-null fibroblasts with KRASG12D and induce an EMT-like phenotype. By providing convincing evidence, the authors were able to derive important insights into KRAS mutant cancers.

eLife assessment

This useful study uses a mouse model of pancreatic cancer to examine mitochondrial mass and structure in atrophying muscle along with aspects of mitochondrial metabolism in the same tissue. Most relevant are the solid transcriptomics and proteomics approaches to map out related changes in gene expression networks in muscle during cancer cachexia.

eLife assessment

This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein, TIPE, regulates aerobic glycolysis to promote tumor growth in melanoma. Data using multiple independent approaches provide new insights into the molecular mechanisms underpinning aerobic glycolysis, also known as the Warburg Effect, in melanoma cells. The claims of the authors are solid, although more in-depth metabolic assays as well as the inclusion of melanoma patient survival analysis in TIPE high and low tumors would strengthen the study. The work will be of interest to biomedical researchers working in cancer and metabolism.

eLife assessment

Given a great need for novel human model systems to study small cell lung cancer (SCLC), the authors describe an important pre-clinical model with broad potential for the study of how genetic perturbations or drug treatments alter SCLC tumor growth, metastasis, and response to therapy. For the major finding, the authors provide convincing evidence that RB/TP53 suppression coupled with MYC overexpression in an ES cell-derived model system results in aggressive and metastatic SCLC. However, comparisons of the RB/TP53-suppressed, MYC overexpressing model with RB/TP53-suppressed cells in supporting the minor conclusion that MYC overexpression increases the neuroendocrine compartment are incomplete, and the impact of the work would have been increased with the inclusion of a broader set of genetic perturbations, such as over-expression of MYCL, to better model major SCLC phenotypes. The new model described will be of significant interest to researchers studying lung cancer.

eLife assessment

This study presents a valuable syngeneic zebrafish model for studying glioblastoma and will be of interest to neuro-oncologists and cancer biologists. Using a feasible in vivo model to study the tumour microenvironment, cell/cell interaction, and immunity, the data are compelling, although the study can benefit from the additional characterization of tumours, as well as non-tumour cells in the niche including microglia/macrophage population.

eLife assessment

This important study using engineered mouse models provides a first compelling demonstration of a pathogenic phenotype associated with lack of expression of p53AS, an isoform of the p53 protein with a different C-terminus as canonical p53. The work also offers correlative evidence that Ackr4, differentially expressed in this mouse model, may be a male-specific prognostic factor in a specific type of B-cell lymphomas. Direct functional evidence testing the links proposed would better support the major findings of the study.

eLife assessment

This study presents fundamental findings that advance our understanding of the role of phenotypic aging in cancer risk. This article presents compelling results that show Phenotypic Age Acceleration (PhenoAgeAccel) can predict cancer incidence of different types and could be used with genetic risk to facilitate the identification of cancer-susceptible individuals. These results will be of broad interest to the research community and clinicians.

eLife assessment:

This valuable manuscript by Go et al. provides an interesting account documenting the role of resident CD56(br) NK cells in driving interaction with DCs that attract CD8+ T cells to the pancreas cancer tumor microenvironment (TME). The work convincingly illustrates how irradiation combined with CCR5i and PD1 blockade leads to a reduction in pancreatic cancer growth that correlates with a reduction in Tregs and enhancement of NK and CD8 T cells in the TME. The correlation of NKC1 signature with survival in pancreatic cancer patients is indeed of broader interest regarding potential relevance to other types of cancer.

eLife assessment

This important study follows up on previous work defining the anti-leukemic effects of a previously characterized cannabis extract on Notch-activated T cells and identifies several pathways that mediate its anti-cancer activity including the ER calcium and integrated stress response. The evidence is solid, but several concerns remain including the over reliance on a single cell line for the majority of the studies and lack of integration of the observations with existing literature

eLife assessment

The large-conductance Ca2+ activated K+ channel BKCa has been reported to promote breast cancer progression. The present study presents convincing evidence that an intracellular subpopulation of this channel reprograms breast cancer cells towards the Warburg phenotype, one of the metabolic hallmarks of cancer. This important finding advances the field of cancer cell metabolism and has potential therapeutic implications.

eLife assessment

The findings in this fundamental study identify a novel substrate and mediator of oncogenesis downstream of mTORC1 and advance our understanding of the mechanistic basis of mTORC1-regulated cap-dependent translation and protein synthesis. The authors present convincing data using an array of biochemical, proteomic, and functional assays. These studies are of broad relevance to biochemists and cancer biologists and have potential translational relevance in cancer.

eLife assessment

The findings provided by Mohibi et al. are important to the field of lipid metabolism and cancer and provide insight for an in vivo role of FDX1. The evidence is solid, utilizing multiple modalities and both in vitro and in vivo lines of investigation.

eLife assessment

Perampalam and colleagues provide solid evidence that Netrin signaling drives survival of non-proliferating ovarian cancer cells and their dissemination. These valuable findings were thought to provide unique insights into the molecular underpinnings of ovarian cancer spread and thus to be of significant interest to cancer biologists. However, the incomplete evidence supporting the role of the described Netrin-dependent mechanism in cancer dormancy was found to be a major shortcoming of the study.

eLife assessment

This study presents fundamental insights into the heterogeneity of chronic myeloid leukemia (CML) stem cells and their response to tyrosine kinase inhibitor therapy, shedding light on potential mechanisms underlying treatment failure. The study's robust methodology, supported by validation with bulk RNA-seq data and surface marker analysis, provides compelling evidence for the identified associations between cellular composition and treatment outcome. These findings contribute to our understanding of CML pathogenesis and may inform the development of more targeted therapeutic strategies.

eLife assessment

This study presents a useful finding on the role of GABRD and its downstream target CDK1 in the progression of breast cancer. The evidence supporting the claims of the authors is somewhat incomplete and the elaboration of the mechanistic details on GABARD/CDK1 regulation would have strengthened the study. The work will be of interest to clinicians and biologists working on breast cancer.

eLife assessment

This important study examined whether the BMP signaling pathway has a role in H3.3K27M DMG tumors, regardless of the presence of ACRVR1 activating mutations. The authors show compelling evidence that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. Although this work could be further enhanced by the inclusion of additional models as well as further consideration of elements, such as the location of the tumor, in the datasets used, overall this work suggests that BMP2/7 could be considered as a target for future therapies in this deadly cancer.

eLife assessment

This study presents a valuable finding on the identification of tumor-reactive T lymphocytes (TRLs) using paired single-cell sequencing and PDX models for cell therapy and marker selection in uveal melanoma treatment. The evidence supporting the claims of the authors is convincing, although the inclusion of detailed explanations of the results for a broader audience would have strengthened the study. The work will be of interest to clinicians and medical biologists working on uveal melanoma (UM).

eLife assessment

The findings of this valuable manuscript advance our understanding of the significance of Bestrophin isoform 4 (BEST4) in suppressing colorectal cancer (CRC) progression. The authors used appropriate and validated methodology, such as the knockout of BEST4 using CRISPR/Cas9 in CRC cells, to provide a solid foundation for elucidating the potential link between BEST4 and CRC progression.

eLife assessment

This important study reports on key characteristics of MYC-driven cancers: dysregulated pre-mRNA splicing and altered metabolism, with the data being overall solid. The manuscript should be of broad interest to cancer biologists due to its therapeutic implications.