Paclitaxel is a cornerstone first-line therapy for ovarian cancer, but its efficacy is limited by chemoresistance. Disulfiram (DSF), an FDA-approved alcohol-aversion drug, shows promising antitumor activity. However, its impact on paclitaxel sensitivity in ovarian cancer and the underlying mechanism remain unclear. This study identified DSF as a reversal agent of paclitaxel resistance. In vitro, DSF's chemosensitizing effect was tested on paclitaxel-resistant and parent ovarian cancer cells. Mechanistic investigations involved examining the triggering of RIPK1/RIPK3/MLKL-regulated necroptosis versus caspase-dependent apoptosis, depending on cellular context. RIPK1 was inhibited with Nec-1, and the direct binding to Apoptosis-inducing factor (AIF) was studied, with AIF knockdown used for validation. In vivo studies were conducted using resistant xenograft models to confirm the anticancer efficacy and observe necroptosis markers. DSF significantly improved paclitaxel chemosensitivity in vitro. Mechanistically, it selectively triggered necroptosis in paclitaxel-resistant cells with higher caspase-8 expression, while promoting apoptosis in cells with lower caspase-8 expression. RIPK1 inhibition impaired DSF-induced necroptosis and chemosensitization. Furthermore, DSF directly bound to AIF, enhancing RIPK1/RIPK3/MLKL phosphorylation and necroptosis activation; this effect was suppressed by AIF knockdown. Crucially, in vivo studies confirmed that DSF boosted the anticancer efficacy of paclitaxel in resistant models, which was accompanied by upregulation of the necroptosis executor p-MLKL and no observable toxicity. Our findings not only unveiled a novel mechanistic basis for the repurposing of DSF but also highlighted AIF-mediated necroptosis as a promising therapeutic strategy to overcome chemoresistance in ovarian cancer.

Breast cancer remains one of the most prevalent malignancies among women, with doxorubicin resistance posing a significant challenge that undermines treatment success and survival outcomes. Aberrant alternative splicing (AS), driven by dysregulation or mutations in splicing factors (SFs), is implicated in cancer initiation, progression, and drug resistance. This study aims to investigate the association of the epithelial cell-specific splicing factor ESRP1 with doxorubicin resistance in breast cancer, focusing on how ESRP1 deficiency correlates with AS changes that promote chemoresistance. We analyzed RNA-sequencing (RNA-seq) data from doxorubicin-resistant (MCF7-DR) and parental (MCF7) breast cancer cell lines to identify enhanced alternative splicing events (ASEs) and changes in ESRP1 expression; we further leveraged The Cancer Genome Atlas (TCGA)-BRCA cohort to construct an SF-RASE correlation network for screening core SFs (including ESRP1). An integrative analysis combining crosslinking immunoprecipitation (CLIP-seq) data and The Cancer Genome Atlas (TCGA) database was performed to validate ESRP1 binding targets and assess the association between ESRP1-related splicing and cytoskeleton organization. We observed extensive AS changes and significantly downregulated ESRP1 expression in MCF7-DR cells. Integrative analysis identified 61 high-confidence ASEs that correlate with ESRP1 expression. Further bioinformatic integration suggests that ESRP1 expression is associated with the splicing patterns of SPTBN1, MAP2K7, FGFR3, and CYB561A3-four genes involved in cytoskeleton organization-though direct experimental verification to confirm a causal regulatory relationship between ESRP1 and the splicing of these genes is still pending. Our findings suggest that ESRP1 expression is closely associated with doxorubicin resistance in breast cancer cells, with concomitant alterations in key ASEs linked to cytoskeletal remodeling that correlate with ESRP1. Exploring the ESRP1-related splicing network may offer new strategies to overcome chemoresistance and improve patient outcomes. However, the small cell line sample size (n = 2 per group) constrains the robustness of ASE and SF-ASE correlation findings, and these results should be interpreted with caution and require further validation with larger sample cohorts.

Young adults' lived experiences of parental cancer: a qualitative evidence synthesis.

Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.

Fighting alone: Caregiving burden and coping strategies among the Chinese only-child "sandwich generation" facing parental cancer.

To establish an analytical method for human DNA contamination with mouse DNA using a DNA methylation microarray. A pure human DNA sample was generated by mixing fully methylated and unmethylated DNA originating from the human cell line HCT116 and fully methylated mouse DNA. The pure human DNA sample, human DNA samples mixed with 30% and 60% mouse DNA, and the pure mouse DNA samples were analyzed using the Infinium MethylationEPIC v2.0 kit. Cell line xenografts (CDX) were prepared from RKO and Pa-Tu-8902 cell lines. We identified 7,446 low-reproducibility probes using pure human DNA samples and 133,377 mouse cross-reacting probes using pure mouse DNA. After excluding these probes, functional probes improved the correlation in methylation levels between pure human DNA samples and those mixed with mouse DNA. Functional probes improved the correlation between DNA methylation levels in human CDX samples and their parental cancer cell lines. Our established method can minimize the effect of mouse DNA contamination in human DNA samples, thereby enabling the analysis of human CDX and patient-derived xenograft (PDX) models.

Drug resistance driven by efflux transporters and altered tubulin dynamics limits the clinical efficacy of taxanes and vincristine in high-risk neuroblastoma (NB) and castration-resistant prostate cancer (CRPC). We developed QW-5-70, a colchicine-binding-site inhibitor (CBSI), engineered to retain low-nanomolar potency in both parental and drug-resistant cancer cells by showing minimal dependence on P-glycoprotein (P-gp)-mediated efflux. QW-5-70 binds to the colchicine site on tubulin, inhibits tubulin polymerization, disrupts microtubule networks, and induces mitotic arrest. Across a panel of NB and prostate cancer lines, QW-5-70 maintained low-nanomolar activity and remained effective in vincristine-resistant BE2C/VCR and paclitaxel-resistant PC-3/TxR cells. Unlike vincristine and paclitaxel, QW-5-70's activity and intracellular accumulation were unaffected by pharmacologic or genetic inhibition of P-gp, indicating effective circumvention of efflux-mediated resistance. In vitro, QW-5-70 significantly reduced colony formation and impaired migration in both parental and resistant cancer cells, and induced G2/M cell cycle arrest and mitochondrial apoptosis. In vivo, QW-5-70 significantly suppressed tumor growth in drug-resistant PC-3/TxR and BE2C/VCR xenografts, with modest weight loss and no evident histopathology in the major organs. Combination studies revealed a combination index (CI)-defined synergistic interactions at selected dose pairs with the ornithine decarboxylase inhibitor DFMO, and enhanced apoptotic and clonogenic suppression when combined with the Aurora A kinase inhibitor MLN8237. Collectively, QW-5-70 is a potent CBSI that circumvents P-gp-associated resistance, triggers mitotic arrest and apoptosis, and achieves significant antitumor activity in multidrug-resistant tumor models with acceptable tolerability, supporting its further preclinical development alone and in combination with other drugs.

ABSTRACTExtracellular vesicle (EV) heterogeneity is well documented but poorly defined. This is especially important in cancer where EVs serve as carriers of unique oncogenic macromolecules that can be transferred to recipient cells or targeted for liquid biopsy diagnostics. Here we employed a series of human glioma cell lines to test the content and distribution of oncogenic epidermal growth factor receptor (EGFR) including its mutant (EGFRvIII) among different subsets of tumour‐derived EVs. Our results suggest that the global levels of EGFR packaged into EVs parallels its expression in parental cancer cells. However, while in glioma cells expressing high levels of EGFR (GSC83) this receptor was uniformly distributed on cellular surfaces, only a small fraction of their derived EVs contained EGFR, as documented by nano‐flow cytometry, ExoView and super‐resolution microscopy. Using only three protein markers (CD63, CD81 and EGFR) these single EV platforms revealed the existence of seven different EV subsets, of which four contained EGFR. Purified EGFR‐positive and negative EVs contained both shared and distinctive protein markers. EGFR packaging into EVs of GSC83 cells was independent of syntenin 1 expression, but was suppressed upon treatment with pharmacological inhibitor of neutral sphingomyelinase (GW4869). Exposure of human microglial cells (HMC3) to EVs released from GW4869‐treated and control glioma cells triggered distinctive changes in cellular proteome including transfer of EGFR. Overall, our results suggest that multiple pathways of EV biogenesis may operate in glioma cells resulting in formation of complex EV landscapes consisting of EGFR‐positive and EGFR‐negative EV subsets. This heterogeneity may have important implications for EV functions and EV‐based diagnostics.

This scoping review aimed to investigate the current knowledge regarding healthy parents' experiences of parenting children and young adults in families affected by parental cancer. Following the Joanna Briggs Institute framework, a systematic search was conducted in MEDLINE, Embase, CINAHL, and PsycINFO. Eligible studies included qualitative and mixed-methods research involving healthy parents of children and young adults (0-28 years) in families where the other parent was diagnosed with cancer, without restrictions on publication year. Studies involving healthy partners of patients in curative and palliative stages were included. Screening was performed independently by two researchers, and data were charted and synthesized, following the thematic analysis approach of Braun and Clarke. Of 3,652 screened articles, 21 articles met the inclusion criteria; qualitative (n = 19), mixed-methods (n = 1), and a qualitative PhD dissertation (n = 1). Four themes emerged: (1) Family Dynamics and Relationships, (2) The Emotional Impact of the Healthy Parent, (3) Coping Strategies and Illness Adaptation, and (4) Support Systems and Everyday Challengers. Healthy parents in families affected by parental cancer play a pivotal role in sustaining family functioning during parental cancer. They experience dual burdens of caregiving and parenting and emotional strain, including insufficient support. Their unmet needs may compromise their parenting capacity and family well-being, underscoring the importance of integrating healthy parents' experiences into family-centered health care and support structures and services. While healthy parents carry the dual responsibilities of caregiving and parenting during parental cancer, their needs and perspectives are often overlooked in oncological care. Recognizing and addressing their needs are essential to protect their parenting capacities and the family's well-being. Integrating healthy parents into family-centered care may enhance experienced resilience and strengthen support for the whole family.

Antiproliferative effects of TUBB3 in ERα-positive postmenopausal breast cancer model cells.

Tumor-induced bone disease (TIBD) arises from a complex interplay between metastatic cancer cells and the bone microenvironment, creating a self-reinforcing “vicious cycle” of bone destruction and tumor growth. Experimental evidence from our group (Buenrostro et al., Bone 113:77-88, 2018) suggests that tumor cells in the bone microenvironment early in disease rely more heavily on bone-derived growth factors, such as transforming growth factor-β (TGF-β), to sustain proliferation than tumor cells late in disease, which may grow independently of these factors. Here, we integrate a mechanistic, population-dynamics model of tumor–bone interactions with in vivo data to test the hypothesis that inhibiting bone resorption suppresses growth of non-adapted but not bone-adapted tumors. The model includes key regulators of TIBD, including TGF-β-driven tumor proliferation, parathyroid hormone-related protein (PTHrP) secretion, and osteoblast (OB)–osteoclast (OC) coupling. Parameter calibration using data from mice injected intratibially with parental (non-adapted) and bone-adapted breast cancer cells reveals distinct parameter values for each tumor type. Bone-adapted cells exhibit a higher basal division rate and reduced sensitivity to TGF-β-mediated stimulation, whereas parental-derived tumor cells depend more strongly on TGF-β and secrete PTHrP at higher rates to compensate for their slower growth. Model simulations reproduce the greater bone loss observed experimentally for bone-adapted tumors and predict that, for non-adapted tumors, bone destruction results from a slower but meaningful rise in OC activity and a possible moderate decline in OBs. Simulated treatment of bone-adapted tumors with the bisphosphonate zoledronic acid stabilizes bone density but has limited or highly variable effects on tumor growth. These results suggest that OC inhibition alone may be insufficient to restrain tumor expansion once tumors have adapted to the bone microenvironment. Together, these findings support the hypothesis that tumor adaptation to the bone microenvironment governs dependence on bone-derived growth factors and response to OC-targeted therapy, underscoring the value of mechanistic modeling for elucidating tumor–bone interactions and guiding tumor-type-specific treatment strategies for TIBD.

In the tumor microenvironment, hypoxia and stromal interactions contribute to enhanced malignant behavior in cancer cells. This study aimed to assess whether pancreatic cancer cells with higher malignancy display stronger responses to hypoxia and stromal cells than their less malignant parental cells, and evaluated the underlying mechanisms, focusing on lysophosphatidic acid (LPA) receptor signaling linked to the acquisition of malignant traits. Highly invasive PANC-M10 cells, derived from the parental pancreatic cancer PANC-1 cells, were cultured at 1% O2 to mimic hypoxic conditions and co-cultured with lymphatic endothelial SVEC4-10 cells. Exposure to 1% O2 increased LPAR2 and LPAR3 expression in PANC-M10 cells. Although cell proliferation in response to LPA treatment in 1% O2 culture also increased in PANC-1 cells, the increase was more pronounced in PANC-M10 cells. PANC-M10 cells displayed markedly elevated invasive activity in 1% O2 compared with PANC-1 cells. This hypoxia-induced invasion was reduced by AM966 (LPA1 antagonist) and GRI-977,143 (LPA2 agonist), while (2S)-OMPT (LPA3 agonist) further enhanced invasive capacity, indicating distinct receptor-dependent functions. Co-culture with SVEC4-10 cells at 1% O2 amplified the invasive behavior of PANC-M10 cells beyond that observed under monoculture. In addition, the supernatant collected from PANC-M10 cells maintained at 1% O2 more effectively stimulated SVEC4-10 tube formation than the supernatant from PANC-1 cells. These findings demonstrate that highly invasive pancreatic cancer cells undergo hypoxia-driven crosstalk with lymphatic endothelial cells, promoting tumor progression through LPA receptor-mediated signaling pathways.

Reprogramming somatic cells to an embryonic state opens a transformative pathway to convert cancer cells into benign ones. By delving into the changes that occur during this process, we can enhance our understanding of tumor development and unlock groundbreaking therapeutic strategies. In this study, we successfully reprogrammed the bladder cancer cell line using Yamanaka factors and conducted a stage-specific, comprehensive proteomic analysis of the resulting molecular changes. The bladder cancer cell line HTB-4 was reprogrammed and cultured on vitronectin-coated surfaces following Sendai virus reprogramming, enabling a thorough evaluation of pluripotent marker expression. Both parental and reprogrammed cells were tested for proliferation, migration, invasion, and colony formation. nLC-MS/MS analysis was performed to identify molecular differences between parental bladder cancer cells and reprogrammed cells across initial passages. Reprogrammed HTB-4 cells retain their ability to adhere and exhibit significant expression of pluripotency-associated proteins, forming colony-like structures. Stage-specific proteomic analyses reveal notable differences between reprogrammed cells and progenitor cells, particularly in pathways related to epithelial-mesenchymal transition, stem cell maintenance, and differentiation. We developed an in vitro model of bladder cancer reprogramming that identifies biomarkers associated with the induction of stem-like states and cellular plasticity. Our findings reveal significant stage-specific proteomic changes offering insights into the hierarchical organization of bladder cancer and the molecular mechanisms underlying the cancer stem cell phenotype. These results facilitate the development of more precise, patient-specific in vitro models for studying tumor recurrence and treatment resistance. However, further mechanistic studies are needed to translate effectively potential biomarkers into clinical practice.

To examine how live birth rates, preterm birth, and major birth defects are affected by parental cancer history and conception method. IVF births were identified by linking the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System to birth certificates in three States. For each IVF-conceived birth, the subsequent 10 naturally conceived births (from birth certificates) created the comparison group. Parental cancer history was identified by linkage to state cancer registries. Preterm birth (PTB) was defined from birth certificates; birth defects (BD) from state BD registries. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for PTB and BDs were calculated with logistic regression. Overall, 30.5% of female cancer survivors who underwent IVF had a live birth. Of 814,658 total births, 9.1% were PT and 4.4% had BDs. IVF was associated with increased risk of PTB and major BDs regardless of parental cancer history. Maternal, but not paternal, cancer history was associated with an increased risk of PTB. No increase in BDs was observed with parental cancer history alone. Risks of both PTB and BDs were highest among multiple births. IVF use was associated with increased risk of PTB and major BDs. Parental cancer history did not elevate the risk of BDs, which remains low. Based on these data, cancer survivors attempting to conceive with or without IVF can be counseled that the magnitude of risk for PTB and major BD was similar for cancer survivors compared with those who conceive without a parental cancer history.

Background Parental advanced lung cancer substantially affects parent–child relationships, particularly with children/adolescents. Objective This study examined interactions, communication patterns, and coping strategies between middle-aged parents with advanced lung cancer and their children/adolescents. Methods Purposive sampling recruited parents with advanced lung cancer and their children/adolescents. Data were collected through in-depth interviews and children’s drawings using interpretative phenomenological analysis. Results 19 parents and 17 children/adolescents participated. Four themes emerged: (1) parental experiences and effects on parental roles; (2) effects on parent–child relationships; (3) children/adolescent’s adjustment to Parental Cancer: physical and psychological; and (4) reconstruction of parent–child interactions and relationships. Families exhibited communication difficulties and emotional distancing, with children desiring love, support, and security. Conclusion Middle-aged parents with advanced lung cancer experience emotional connection difficulties. Practical implications Family-centred support is essential for strengthening communication, emotional bonding, and coping strategies.

Ferroptosis has emerged as a promising therapeutic strategy for drug-resistant cancers; however, the molecular mechanisms governing ferroptosis susceptibility in breast cancer remain poorly defined. Here, we have investigated distinct ferroptosis resistance mechanisms in parental MCF-7 breast cancer cells and their BCRP-overexpressing derivative, MCF-7/MXR. MCF-7/MXR cells displayed robust erastin (ER)-induced ferroptosis characterized by extensive lipid peroxidation, ROS accumulation, and suppression of the xCT-GSH-GPX4 axis. In contrast, MCF-7 cells were resistant to ER, exhibiting minimal lipid damage despite measurable ER-induced oxidative stress. We found that this resistance is mediated not by the canonical GPX4 pathway, but by a potent compensatory antioxidant system centered on the FSP1-CoQ10-NADPH axis. Pharmacological inhibition of FSP1 strongly sensitized MCF-7 cells to ER, with minimal effects in MXR cells. ER differentially regulated ferroptosis-associated genes, downregulating GPX4, and SLC7A11 in MXR cells but upregulating the GPX4 pathway in MCF-7 cells. Additionally, ER downregulated FSP1 and NQO1 in MCF-7 cells without affecting their expressions in MXR cells. This mechanistic divergence highlights that ferroptosis resistance in breast cancer is context-dependent and mediated by pathway-specific antioxidant programs. Co-targeting FSP1 and GPX4 therefore represents a rational strategy to overcome ferroptosis resistance in MCF-7-like breast cancers.

Cancer cell reprogramming is a critical area of research that holds the power to transform malignancies into benign states while revealing key mechanisms of carcinogenesis. This study aimed to develop a more effective in vitro bladder cancer model using induced pluripotent stem cell technology and identify potential diagnostic and therapeutic biomarkers for bladder cancer. Sendai virus-based reprogramming was utilised to reprogram the bladder cancer cell line HTB-5. The reprogrammed cells were characterised by expressing pluripotency-associated markers, colony formation abilities, cell migration, and drug responses. LC-MS/MS reveals changes in protein composition among parental cancer cells, reprogrammed cancer cells, and normal uroepithelial cells. Reprogrammed bladder cancer cells display the expression of pluripotency-associated markers and demonstrate altered behaviours, including cell migration and responses to anticancer therapies. The genome-wide regulation by Sendai-virus delivery of Yamanaka factors resulted in distinctive protein expression patterns in reprogrammed bladder cancer cells, indicative of the pluripotency as well as spontaneous differentiation. A total of 297 dysregulated proteins in bladder cancer cells were normalised upon reprogramming. We proposed 25 potential biomarker candidates for diagnostic and therapeutic purposes, of which 12 candidates were demonstrated for the first time at the protein level. Differentially regulated proteins in parental bladder cancer cells and reprogrammed bladder cancer cells highlighted the critical protein-protein interactions that indicate the normalisation process of the parental bladder cancer cells. These cues could be used to pinpoint the candidate proteins to optimise the controlled partial/full reprogramming, to discover the therapeutic potential of reprogramming and to propose clinically relevant biomarker candidates.

Polyploid cisplatin-resistant cancer cells have altered nuclear organization and epigenomic status.

ABSTRACTObjectiveChildren and adolescents confronted with parental cancer are highly vulnerable. During such a family crisis, the social environment and external institutions (e.g., kindergarten, school) can play a crucial role in providing stability and support. This study aims to adapt and pilot‐test an existing training program on parental cancer for educational professionals.MethodThis study is divided into three phases: (1) conducting qualitative interviews with parents with cancer, their children and educational professionals, (2) adapting an existing training program for healthcare professionals to the context of educational professionals, and (3) pilot‐testing the training program using quantitative and qualitative methods.ResultsInterview results indicate that school is an important place to provide normality and stability. Parents appreciated it when educational professionals took the initiative by offering conversations, support and practical help. The adaptation resulted in a 3‐h training and was provided for n = 8 voluntary educational professionals. Preliminary results indicate that participants felt more knowledgeable, confident and empathic towards affected families after the training.ConclusionPreliminary findings indicate that the training is a feasible approach to enhance knowledge and self‐confidence of educational professionals in dealing with families affected by parental cancer. To validate these findings from a small study sample, further research is needed.

Children of parents with cancer face elevated risks of anxiety, depression, and impaired social-emotional functioning. Cancer support camps may mitigate these psychosocial challenges by fostering connection, resilience, and expression. However, no validated tools exist to measure quality of life outcomes specific to this context. This study aimed to develop and evaluate the Kids' Experience of Summer Enrichment Measure (KESEM), a parent-report tool assessing psychosocial well-being among children attending a cancer support camp due to a parent's cancer. A secondary analysis of survey data collected from 2021 to 2024 by a national non-profit providing free, week-long summer camps to children (aged 6-18) affected by parental cancer was conducted. The KESEM, a new 12-item measure embedded in post-camp evaluations, was examined using principal components factor analysis and internal consistency reliability testing: convergent validity was assessed as well. Responses from N = 1802 parents and N = 184 children were studied. Analysis revealed a two-factor structure: (i) Well-being and Belonging (α = 0.93) and (ii) Empowerment (α = 0.92)-accounting for 67.2% of the measure's variance. The total scale demonstrated high internal consistency (α = 0.94). In subgroup analysis, parent and child scores supported convergent validity of parental reporting on children's quality of life, and were not influenced by child age: F (1, 168) = 0.03, p = 0.87. Concordantly, the majority of parents (78%) strongly agreed that camp was favorably impactful and would recommend it to others. The KESEM is a promising parent-reported assessment tool for measuring quality of life outcomes in children attending cancer support camps. Such camps may offer meaningful psychosocial benefits to children coping with parental cancer.