Trophoblast 'pseudo-tumorigenesis': Significance and contributory factors

Trophoblast cells of the human placenta proliferate, migrate, and invade the pregnant uterus and its vasculature in order to nourish the developing fetus, in a way that is imitated by malignant tumors. Many similarities exist between embryo implantation and the growth of cancer cells. We begin this article by reviewing decades of studies that have helped unearth the mechanisms that contribute to the tumor-like phenotype of human trophoblast cells. Interestingly, these attributes are only transient in nature, with stringent spatial and temporal confines. The importance of intrinsic molecular controls that effectively circumscribe the extent and duration of trophoblast incursion, becomes increasingly evident in abnormal pregnancies that are characterized by aberrant trophoblast proliferation/invasion. We summarize and discuss the significance of abnormalities in these regulatory mechanisms, and finally, speculate about the use of human trophoblastic cells as model systems for the study of a variety of cellular processes. While on one hand, human placental cells are bestowed with a capacity to proliferate indefinitely and invade extensively, on the other, these cells are also replete with mechanisms to regulate these tumor-like attributes and eventually progress to a senescent apoptotic state. This is therefore, a 'well-behaved' tumor. The comparison in the present review is between the invasive cytotrophoblastic cell type and the tumor cell type

Lineage Plasticity and Stemness Phenotypes in Prostate Cancer: Harnessing the Power of Integrated Omics Approaches to Explore Measurable Metrics

Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic cells to undergo phenotypic changes under microenvironmental pressures by switching between developmental cell states. What remains to be elucidated is how to identify measurements of lineage plasticity, how to implement them to inform preclinical and clinical research, and, further, how to classify patients and inform therapeutic strategies in the clinic. Recent research has highlighted the crucial role of next-generation sequencing technologies in identifying potential biomarkers associated with lineage plasticity. Here, we review the genomic, transcriptomic, and epigenetic events that have been described in PCa and highlight those with significance for lineage plasticity. We further focus on their relevance in PCa research and their benefits in PCa patient classification. Finally, we explore ways in which bioinformatic analyses can be used to determine lineage plasticity based on large omics analyses and algorithms that can shed light on upstream and downstream events. Most importantly, an integrated multiomics approach may soon allow for the identification of a lineage plasticity signature, which would revolutionize the molecular classification of PCa patients

A Structured Curriculum Supporting Biomedical Trainees’ Transition Into Independent Academic Positions and Early Career Success

The United States government makes a substantial investment in biomedical training programs each year. However, for most trainees, these opportunities do not translate into career progression in academic research pathways. Only about one-fifth of postdoctoral fellows eventually secure a tenure-track faculty position, and even among these candidates, attrition is high. Although a number of factors govern career choices and career longevity, the transition from trainee to faculty is a challenging process and requires knowledge and skills that are not necessarily developed during a traditional university experience. Many postdoctoral fellows receive adequate training in research skills and scientific communication, but new faculty report not being sufficiently prepared for the job search process and for starting their labs. To address this critical training gap, the ITERT core (Interdisciplinary Translational Education and Research Training) and the Office of Postdoctoral Fellows at the University of Texas MD Anderson Cancer Center implemented a structured course for both postdoctoral fellows and senior PhD students to provide formalized training for successfully navigating academic positions in biomedical research. Here we report on the pilot Navigating Academic Careers course conducted in 2021-2022 for 30 PhD students and postdocs. The nine-module course was conducted over 13 weeks in 25.5 h instructional sessions. The key educational objectives included 1) navigating the job application and the interview/negotiation process, 2) hiring, leading, and mentoring lab personnel and program support staff, 3) project administration and financial stewardship, 4) managing time and work-life balance and 5) developing collaborations, branding, personalized niche, and networking. Survey-based analysis at the time of the course was used to capture the participants\u27 assessment of the course content, organization, and delivery, with a follow-up survey conducted approximately 2 years post-course (2024) to evaluate longer-term impacts of the training. Initial in-course assessment revealed that 89.9% of respondents found the scope and instructional content appropriate, and 91.1% found the course relevant and applicable to their career needs. Longer-term post-course evaluation indicated that 80% of respondents applied the learnings of the course, that 80% reported feeling more confident in navigating an academic job search, and that 66.6% continued to report agreement with the course preparing them for their current role/ongoing job search, with 46.7% already securing jobs in academic research, including as independent faculty. The outcomes of this pilot course suggest that integrating this into the broader postdoctoral training curriculum can enhance both the transition and early-career success of talented scientists-in-training into working professionals in biomedical careers, as faculty and science-trained staff

Primate epididymis-specific proteins: characterization of ESC42, a novel protein containing a trefoil-like motif in monkey and human

Epididymal secreted proteins promote sperm maturation and fertilizing capacity by interacting with sperm during passage through the epididymis. Here we investigate the molecular basis of sperm maturation by isolating cDNA clones for novel epididymis-specific expressed sequences. Thirty-six novel cDNAs were isolated and sequenced from a subtracted Macaca mulatta epididymis library. The clones encode proteins with a range of motifs characteristic of protein-modifying enzymes, protease inhibitors, hydrophobic ligand-binding and transport proteins, extracellular matrix-interacting proteins, and transcription regulatory factors. The full length coding sequences were obtained for 11 clones representing a range of abundance levels. Expression of each is regionally localized and androgen regulated. The most abundant, ESC42, contains a cysteine-rich region similar to the signature binding domain of the trefoil family of motogenic wound repair proteins. The monkey and human proteins are nearly 90% identical. Immunohistochemical staining revealed that the protein is most abundant in the epithelium of the caput and is also present in the lumen and bound to sperm. The ESC42 gene, located on chromosome 20q11, contains two exons encoding two nearly identical predicted signal peptides and a third exon encoding the rest of the protein

LCN6, a novel human epididymal lipocalin

BACKGROUND: The lipocalin (LCN) family of structurally conserved hydrophobic ligand binding proteins is represented in all major taxonomic groups from prokaryotes to primates. The importance of lipocalins in reproduction and the similarity to known epididymal lipocalins prompted us to characterize the novel human epididymal LCN6. METHODS AND RESULTS: LCN6 cDNA was identified by database analysis in a comprehensive human library sequencing program. Macaca mulatta (rhesus monkey) cDNA was obtained from an epididymis cDNA library and is 93% homologous to the human. The gene is located on chromosome 9q34 adjacent LCN8 and LCN5. LCN6 amino acid sequence is most closely related to LCN5, but the LCN6 beta-barrel structure is best modeled on mouse major urinary protein 1, a pheromone binding protein. Northern blot analysis of RNAs isolated from 25 human tissues revealed predominant expression of a 1.0 kb mRNA in the epididymis. No other transcript was detected except for weak expression of a larger hybridizing mRNA in urinary bladder. Northern hybridization analysis of LCN6 mRNA expression in sham-operated, castrated and testosterone replaced rhesus monkeys suggests mRNA levels are little affected 6 days after castration. Immunohistochemical staining revealed that LCN6 protein is abundant in the caput epithelium and lumen. Immunofluorescent staining of human spermatozoa shows LCN6 located on the head and tail of spermatozoa with the highest concentration of LCN6 on the post-acrosomal region of the head, where it appeared aggregated into large patches. CONCLUSIONS: LCN6 is a novel lipocalin closely related to Lcn5 and Lcn8 and these three genes are likely products of gene duplication events that predate rodent-primate divergence. Predominant expression in the epididymis and location on sperm surface are consistent with a role for LCN6 in male fertility

Evaluation of the Aggressive-Variant Prostate Cancer Molecular Signature in Clinical Laboratory Improvement Amendments (CLIA) Environments

Aggressive-variant prostate cancers (AVPCs) are a subset of metastatic castrate-resistant prostate cancers (mCRPCs) characterized by defects in ≥ two of three of TP53, RB1, and PTEN (AVPCm), a profile linked to lineage plasticity, androgen indifference, and platinum sensitivity. Men with mCRPC undergoing biopsies for progression were assessed for AVPCm using immunohistochemistry (IHC), next-generation sequencing (NGS) of solid tumor DNA (stDNA), and NGS of circulating tumor DNA (ctDNA) assays in CLIA-certified labs. Biopsy characteristics, turnaround times, inter-reader concordance, and inter-assay concordance were assessed. AVPCm was detected in 13 (27%) patients via IHC, two (6%) based on stDNA, and seven (39%) based on ctDNA. The concordance of the IHC reads between pathologists was variable. IHC had a higher detection rate of AVPCm+ tumors with the shortest turnaround times. stDNA had challenges with copy number loss detection, limiting its detection rate. ctDNA detected the greatest proportion of AVPCm+ tumors but had a low tumor content in two thirds of patients. These data show the operational characteristics of AVPCm detection using various assays, and inform trial design using AVPCm as a criterion for patient selection or stratification

Pan-Cancer Proteogenomics Characterization of Tumor Immunity

Despite the successes of immunotherapy in cancer treatment over recent decades, less than \u3c10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents