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Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin’s effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression. Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.

Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model in mice and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer. Although there have been considerable improvements in breast cancer treatments over the years, there are still many patients whose cancerous cells become resistant to treatments, including chemotherapy. Several different factors can contribute to resistance to chemotherapy, but one important change is the epithelial-to-mesenchymal transition (or EMT for short). During this transition, breast cancer cells become more aggressive, and more able to metastasize and spread to other parts of the body. Cells can also go through the reverse process called the mesenchymal-to-epithelial transition (or MET for short). Together, EMT and MET help breast cancer cells become resilient to treatment. However, it was not clear if these transitions shared a mechanism or pathway that could be targeted as a way to make cancer treatments more effective. To investigate, Ban, Zou et al. studied breast cancer cells from mice which had been labelled with fluorescent proteins that indicated whether a cell had ever transitioned between an epithelial and mesenchymal state. Various genetic experiments revealed that breast cancer cells in the EMT or MET phase made a lot more ribosomes, molecules that are vital for producing new proteins. Ban, Zhou et al. found that blocking the production of ribosomes (using drugs or genetic tools) prevented the cells from undergoing both EMT and MET. Further experiments showed that when mice with breast cancer were treated with a standard chemotherapy treatment plus an anti-ribosome drug, this reduced the number and size of tumors that had metastasized to the lung. This suggests that blocking ribosome production makes breast cancer cells undergoing EMT and/or MET less resistant to chemotherapy. Future studies will have to ascertain whether these findings also apply to patients with breast cancer. In particular, one of the drugs used to block ribosome production in this study is in early-phase clinical trials, so future trials may be able to assess the drug’s effect in combination with chemotherapies.

The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.

Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process. Platelets have been associated with increased tumor growth and metastasis but the mechanistic details of this interaction are still unclear. Here the authors show that platelets improve anoikis resistance of cancer cells and increase metastasis by activating Yap through a RhoA/MYPT-PP1 pathway.

This study developed a highly efficient serum‐free pluripotent stem cell (PSC) neural induction medium that can induce human PSCs into primitive neural stem cells (NSCs) in 7 days, obviating the need for time‐consuming, laborious embryoid body generation or rosette picking. This method of primitive NSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions. Human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, are unique cell sources for disease modeling, drug discovery screens, and cell therapy applications. The first step in producing neural lineages from hPSCs is the generation of neural stem cells (NSCs). Current methods of NSC derivation involve the time‐consuming, labor‐intensive steps of an embryoid body generation or coculture with stromal cell lines that result in low‐efficiency derivation of NSCs. In this study, we report a highly efficient serum‐free pluripotent stem cell neural induction medium that can induce hPSCs into primitive NSCs (pNSCs) in 7 days, obviating the need for time‐consuming, laborious embryoid body generation or rosette picking. The pNSCs expressed the neural stem cell markers Pax6, Sox1, Sox2, and Nestin; were negative for Oct4; could be expanded for multiple passages; and could be differentiated into neurons, astrocytes, and oligodendrocytes, in addition to the brain region‐specific neuronal subtypes GABAergic, dopaminergic, and motor neurons. Global gene expression of the transcripts of pNSCs was comparable to that of rosette‐derived and human fetal‐derived NSCs. This work demonstrates an efficient method to generate expandable pNSCs, which can be further differentiated into central nervous system neurons and glia with temporal, spatial, and positional cues of brain regional heterogeneity. This method of pNSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions.

Background/Objectives: Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. Methods: To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for the validation of discovered subtypes and to add spatial context. Results: Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T cells, and LAMP3+ dendritic cells. Conclusions: Using cell–cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche.

KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3′ UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.

The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo . Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment. An epithelial-to-mesenchymal transition (EMT) lineage-tracing system in a mouse model of breast-to-lung metastasis reveals that although some cells undergo EMT in a primary epithelial tumour, the lung metastases mainly arise from cells that have not undergone EMT; in addition, cells that have undergone EMT appear more resistant to chemotherapy. No requirement for EMT in metastasis It has been suggested that epithelial-to-mesenchymal transition (EMT), in which epithelial cells depolarize and adopt a fibroblast-like morphology, is a requirement for metastasis to occur. Other studies imply that the importance of EMT relies on cell-culture-based manipulation of EMT regulators. In this issue of Nature , two groups present results that suggest that EMT is not a prerequisite for metasasis. Dingcheng Gao and colleagues trace the fate of cells that have undergone EMT in mouse model for breast-to-lung metastasis. They find that although some cells undergo EMT in a primary epithelial tumour, the lung metastases mainly contain cells that have not undergone EMT. However, cells that have undergone EMT appear more resistant to chemotherapy. A microRNA that targets key EMT regulators is shown not to affect metastasis, but to reduce survival of EMT cells following chemotherapy. Raghu Kalluri and colleagues delete Twist or Snail — transcription factors that induce EMT — in a mouse model for pancreatic ductal adenocarcinoma. This leads to an increase in cell proliferation, and a greater sensitivity to chemotherapeutic agent gemcitabine, with no effect on invasion and metastasis.

Background Global epidemiological studies involving over nine million participants have shown a 35% lower incidence of Alzheimer’s Disease (AD) in older cancer survivors compared to those without a history of cancer. This inverse relationship, consistent across recent studies with methodological controls, suggests that cancer itself, rather than cancer treatments, may offer protective factors against AD. This insight opens avenues for novel therapeutic strategies targeting early AD by harnessing cancer‐associated protective factors. Methods To investigate the potential protective effect of cancer against Alzheimer’s Disease (AD), we developed “cancer‐in‐AD” mouse models. These models involved injecting a small number of breast cancer cells into young AD‐model mice (5xFAD) and monitoring amyloid plaque progression. Additionally, we introduced extracellular vesicles (EVs) from breast tumor‐bearing mice into similar AD models. Using spatial transcriptomics, we analyzed brain tissue gene expression and cell‐cell interactions, focusing on the astrocyte‐microglia‐oligodendrocyte network near amyloid plaques. This approach helped identify potential drugs for repurposing in AD treatment. Results The study found a significant reduction in amyloid burden within the brains of the cancer‐in‐AD mouse models compared to age‐matched cancer‐free AD mice. The administration of EVs from cancer animal’s plasma to the AD mice prompted the release of various inflammatory cytokines and chemokines. A key discovery was an activated astrocyte‐microglia‐oligodendrocyte signaling network that regulates amyloid‐beta homeostasis in these mouse brains. Out of 49 FDA‐approved drugs identified to induce this cancer‐induced signaling, 11 showed promise in improving AD symptoms and reducing amyloid and tau accumulations, in both preclinical and clinical studies. Conclusions The study reveals a notable decrease in amyloid levels in AD mice with cancer or exposed to tumor‐derived EVs, linked to immune system reprogramming and glial network activation. This supports the study’s drug repositioning approach and sets the stage for further research into the anti‐AD properties of these drugs, focusing on identifying crucial signaling elements for enhanced drug repositioning and combination treatment strategies.