Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.

Among breast cancers, triple-negative breast cancer (TNBC) is the most poorly understood and is refractory to current targeted therapies. Using a genetic screen, we identify the PTPN12 tyrosine phosphatase as a tumor suppressor in TNBC. PTPN12 potently suppresses mammary epithelial cell proliferation and transformation. PTPN12 is frequently compromised in human TNBCs, and we identify an upstream tumor-suppressor network that posttranscriptionally controls PTPN12. PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR. The tumorigenic and metastatic potential of PTPN12-deficient TNBC cells is severely impaired upon restoration of PTPN12 function or combined inhibition of PTPN12-regulated tyrosine kinases, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting proto-oncogenic tyrosine kinases in TNBC and other cancers based on their profile of tyrosine-phosphatase activity.

Epigenetic markers and therapeutic targets for metastasis.

The last few years have seen an increasing number of discoveries which collectively demonstrate that histone and DNA modifying enzyme modulate different stages of metastasis. Moreover, epigenomic alterations can now be measured at multiple scales of analysis and are detectable in human tumors or liquid biopsies. Malignant cell clones with a proclivity for relapse in certain organs may arise in the primary tumor as a consequence of epigenomic alterations which cause a loss in lineage integrity. These alterations may occur due to genetic aberrations acquired during tumor progression or concomitant to therapeutic response. Moreover, evolution of the stroma can also alter the epigenome of cancer cells. In this review, we highlight current knowledge with a particular emphasis on leveraging chromatin and DNA modifying mechanisms as biomarkers of disseminated disease and as therapeutic targets to treat metastatic cancers.

Tumor self-seeding by circulating cancer cells.

Cancer cells that leave the primary tumor can seed metastases in distant organs, and it is thought that this is a unidirectional process. Here we show that circulating tumor cells (CTCs) can also colonize their tumors of origin, in a process that we call "tumor self-seeding." Self-seeding of breast cancer, colon cancer, and melanoma tumors in mice is preferentially mediated by aggressive CTCs, including those with bone, lung, or brain-metastatic tropism. We find that the tumor-derived cytokines IL-6 and IL-8 act as CTC attractants whereas MMP1/collagenase-1 and the actin cytoskeleton component fascin-1 are mediators of CTC infiltration into mammary tumors. We show that self-seeding can accelerate tumor growth, angiogenesis, and stromal recruitment through seed-derived factors including the chemokine CXCL1. Tumor self-seeding could explain the relationships between anaplasia, tumor size, vascularity and prognosis, and local recurrence seeded by disseminated cells following ostensibly complete tumor excision.

WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.

Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymph node-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus, a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.

Questioning the Impact of Vestibular Rehabilitation in Mal de Debarquement Syndrome.

INTRODUCTION: Mal de debarquement syndrome (MdDS) is a rare and poorly understood clinical entity defined as a persistent sensation of rocking and swaying that can severely affect the quality of life. To date, the treatment options are very limited. Even though vestibular rehabilitation (VR) efficacy following peripheral vestibular lesion is well-documented, little is known about its influence on MdDS. The objective of the study was to explore the influence of traditional VR program on postural control in a patient diagnosed with MdDS. METHODS: We assessed 3 different participants: 1 healthy control; 1 participant with identified peripheral vestibular impairment (VI); 1 participant diagnosed with MdDS. Postural control was assessed using a force plate (AMTI, Accusway). Participants were assessed following the modified Clinical Test Sensory Integration Balance protocol (mCTSIB, eyes open on firm surface/eyes closed on firm surface/eyes open on foam/eyes closed on foam). The raw data were exported and analyzed in a custom-made Matlab script (Matlab R2020a). We retrieved the center of pressure velocity in both anterior-posterior and mediolateral directions and performed an analysis of the frequency content using Daubechies wavelet of order 4 with 6 levels of decomposition. Protocol VI and MdDS patients performed a 4-week VR program. Postural control, using a force plate, and Dizziness Handicap Inventory (DHI) were assessed before and after the VR program. Healthy control was assessed twice separated by 1 week without any specific intervention. RESULTS: VI participant showed clear improvement on DHI and sway velocity on condition eyes closed with foam. Accordingly, a reduction of energy content within frequency bands (0.39-0.78 Hz and 0.78-1.56 Hz) was observed post-rehabilitation for VI participant in both conditions with foam. Interestingly, MdDS participant demonstrated a reduction in sway velocity in most of the conditions but the frequency content was not modified by VR and was comparable to healthy control. Accordingly, the DHI of the MdDS participant failed to demonstrate any difference following VR. CONCLUSION: The results of the present study question the use of VR as an efficient treatment option for MdDS. Future studies must recruit a larger sample size and focus on the relationship between illusion of movement and postural characteristics such as sway velocity.

Lesbian, Gay, Bisexual, Transgender, and Queer (LGBTQ+) Communities and the Coronavirus Disease 2019 Pandemic: A Call to Break the Cycle of Structural Barriers.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately impacted lesbian, gay, bisexual, transgender, and queer (LGBTQ+) communities. Many disparities mirror those of the human immunodeficiency virus (HIV)/AIDS epidemic. These health inequities have repeated throughout history due to the structural oppression of LGBTQ+ people. We aim to demonstrate that the familiar patterns of LGBTQ+ health disparities reflect a perpetuating, deeply rooted cycle of injustice imposed on LGBTQ+ people. Here, we contextualize COVID-19 inequities through the history of the HIV/AIDS crisis, describe manifestations of LGBTQ+ structural oppression exacerbated by the pandemic, and provide recommendations for medical professionals and institutions seeking to reduce health inequities.

Enhancement of dairy sheep cheese eating quality with increased n-3 long-chain polyunsaturated fatty acids.

This study investigated the effect of different plant oil-infused and rumen-protected wheat-based pellets containing eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) on n-3 long-chain (≥C20) polyunsaturated fatty acid (LC-PUFA) content, fatty acid recovery, and sensory attributes of ripened cheese from dairy sheep. During a 10-wk supplementary feeding trial, 60 dairy ewes balanced by live weight, milk yield, parity, and sire breed were randomly divided into 6 groups that were (1) supplemented with on-farm existing commercial wheat-based pellets without oil inclusion (control) or supplemented with wheat-based pellets infused with 50 mL/kg dry matter of oils from (2) canola, (3) rice bran, (4) flaxseed, (5) safflower, and (6) rumen-protected EPA + DHA. Milk samples from each treatment were collected separately by sire breed during the experimental period for cheese processing at the end of the experiment. Twelve batches of cheese (2 batches per treatment) were processed and ripened for 120 d. Three cheese samples were collected and analyzed for each cheese making session (total of 36 cheese samples) at d 120 of ripening. Processed cheese of rumen-protected EPA + DHA had the most efficiency at elevating total n-3 LC-PUFA [total EPA + DHA + docosapentaenoic acid (DPA, 22:5n-3] content compared with the control (0.49 vs. 0.28%). Flaxseed elicited the greatest enhancement of α-linolenic acid (ALA, 18:3n-3), whereas safflower was the most effective diet in enhancing the level of linoleic acid (18:2n-6) in cheese (1.29 vs. 0.71% and 4.8 vs. 3.3%, respectively). Parallel recoveries of n-3 and n-6 LC-PUFA were observed across all treatments except for α-linolenic acid and EPA. Cheese eating sensory traits were also highly affected by oil supplementation, with the highest score of 7.5 in cheese from the rice bran and flaxseed treatments. These results provide new insights into the biological mechanisms and processes that determine dairy ewe milk productivity by underpinning the vital biological role of n-3 LC-PUFA in not only enhancing the healthy composition of cheese from ewes but also translating it into consumer acceptability.

The neural dynamics of competition resolution for language production in the prefrontal cortex.

Previous research suggests a pivotal role of the prefrontal cortex (PFC) in word selection during tasks of confrontation naming (CN) and verb generation (VG), both of which feature varying degrees of competition between candidate responses. However, discrepancies in prefrontal activity have also been reported between the two tasks, in particular more widespread and intense activation in VG extending into (left) ventrolateral PFC, the functional significance of which remains unclear. We propose that these variations reflect differences in competition resolution processes tied to distinct underlying lexico-semantic operations: Although CN involves selecting lexical entries out of limited sets of alternatives, VG requires exploration of possible semantic relations not readily evident from the object itself, requiring prefrontal areas previously shown to be recruited in top-down retrieval of information from lexico-semantic memory. We tested this hypothesis through combined independent component analysis of functional imaging data and information-theoretic measurements of variations in selection competition associated with participants' performance in overt CN and VG tasks. Selection competition during CN engaged the anterior insula and surrounding opercular tissue, while competition during VG recruited additional activity of left ventrolateral PFC. These patterns remained after controlling for participants' speech onset latencies indicative of possible task differences in mental effort. These findings have implications for understanding the neural-computational dynamics of cognitive control in language production and how it relates to the functional architecture of adaptive behavior.

The impact of perilaryngeal vibration on the self-perception of loudness and the Lombard effect.

The role of somatosensory feedback in speech and the perception of loudness was assessed in adults without speech or hearing disorders. Participants completed two tasks: loudness magnitude estimation of a short vowel and oral reading of a standard passage. Both tasks were carried out in each of three conditions: no-masking, auditory masking alone, and mixed auditory masking plus vibration of the perilaryngeal area. A Lombard effect was elicited in both masking conditions: speakers unconsciously increased vocal intensity. Perilaryngeal vibration further increased vocal intensity above what was observed for auditory masking alone. Both masking conditions affected fundamental frequency and the first formant frequency as well, but only vibration was associated with a significant change in the second formant frequency. An additional analysis of pure-tone thresholds found no difference in auditory thresholds between masking conditions. Taken together, these findings indicate that perilaryngeal vibration effectively masked somatosensory feedback, resulting in an enhanced Lombard effect (increased vocal intensity) that did not alter speakers' self-perception of loudness. This implies that the Lombard effect results from a general sensorimotor process, rather than from a specific audio-vocal mechanism, and that the conscious self-monitoring of speech intensity is not directly based on either auditory or somatosensory feedback.

MS/MS networking guided analysis of molecule and gene cluster families.

The ability to correlate the production of specialized metabolites to the genetic capacity of the organism that produces such molecules has become an invaluable tool in aiding the discovery of biotechnologically applicable molecules. Here, we accomplish this task by matching molecular families with gene cluster families, making these correlations to 60 microbes at one time instead of connecting one molecule to one organism at a time, such as how it is traditionally done. We can correlate these families through the use of nanospray desorption electrospray ionization MS/MS, an ambient pressure MS technique, in conjunction with MS/MS networking and peptidogenomics. We matched the molecular families of peptide natural products produced by 42 bacilli and 18 pseudomonads through the generation of amino acid sequence tags from MS/MS data of specific clusters found in the MS/MS network. These sequence tags were then linked to biosynthetic gene clusters in publicly accessible genomes, providing us with the ability to link particular molecules with the genes that produced them. As an example of its use, this approach was applied to two unsequenced Pseudoalteromonas species, leading to the discovery of the gene cluster for a molecular family, the bromoalterochromides, in the previously sequenced strain P. piscicida JCM 20779(T). The approach itself is not limited to 60 related strains, because spectral networking can be readily adopted to look at molecular family-gene cluster families of hundreds or more diverse organisms in one single MS/MS network.

Anaerobic Co-Digestion of Microalgae Scenedesmus sp. and TWAS for Biomethane Production.

The paper investigated the feasibility of biomethane (bio-CH4) production from the anaerobic co-digestion of the microalgae Scenedesmus quadricauda (S. quadricauda) and thickened waste activated sludge (TWAS). The concept was tested in bench-scale anaerobic digesters by varying the proportions of volatile solids (VS) loading from S. quadricauda and TWAS and two critical operational parameters, temperature and alkalinity. The CH(4) production for the various S. quadricauda and TWAS proportions ranged from 234 to 318 mL/g of chemical oxygen demand (COD) digested and 329 to 530 mL/g of VS digested at 35 °C. The reductions in total solids (TS), COD, and VS ranged from 25 to 44%, 46 to 53%, and 40 to 53%, respectively. Temperature had a significant effect on CH(4) production, lower temperatures greatly reduced CH(4) production. No significant difference in CH(4) production was observed for experiments conducted at alkalinity levels of 70, 1630, and 3200 mg/L as CaCO(3).

Pep2Path: automated mass spectrometry-guided genome mining of peptidic natural products.

Nonribosomally and ribosomally synthesized bioactive peptides constitute a source of molecules of great biomedical importance, including antibiotics such as penicillin, immunosuppressants such as cyclosporine, and cytostatics such as bleomycin. Recently, an innovative mass-spectrometry-based strategy, peptidogenomics, has been pioneered to effectively mine microbial strains for novel peptidic metabolites. Even though mass-spectrometric peptide detection can be performed quite fast, true high-throughput natural product discovery approaches have still been limited by the inability to rapidly match the identified tandem mass spectra to the gene clusters responsible for the biosynthesis of the corresponding compounds. With Pep2Path, we introduce a software package to fully automate the peptidogenomics approach through the rapid Bayesian probabilistic matching of mass spectra to their corresponding biosynthetic gene clusters. Detailed benchmarking of the method shows that the approach is powerful enough to correctly identify gene clusters even in data sets that consist of hundreds of genomes, which also makes it possible to match compounds from unsequenced organisms to closely related biosynthetic gene clusters in other genomes. Applying Pep2Path to a data set of compounds without known biosynthesis routes, we were able to identify candidate gene clusters for the biosynthesis of five important compounds. Notably, one of these clusters was detected in a genome from a different subphylum of Proteobacteria than that in which the molecule had first been identified. All in all, our approach paves the way towards high-throughput discovery of novel peptidic natural products. Pep2Path is freely available from http://pep2path.sourceforge.net/, implemented in Python, licensed under the GNU General Public License v3 and supported on MS Windows, Linux and Mac OS X.

Genes that mediate breast cancer metastasis to the brain.

The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway.

INTRODUCTION: The recently identified claudin-low subtype of breast cancer is enriched for cells with stem-like and mesenchymal-like characteristics. This subtype is most often triple-negative (lacking the estrogen and progesterone receptors (ER, PR) as well as lacking epidermal growth factor 2 (HER2) amplification) and has a poor prognosis. There are few targeted treatment options available for patients with this highly aggressive type of cancer. METHODS: Using a high throughput inhibitor screen, we identified high expression of glioma-associated oncogene homolog 1 (GLI1), the effector molecule of the hedgehog (Hh) pathway, as a critical determinant of cell lines that have undergone an epithelial to mesenchymal transition (EMT). RESULTS: High GLI1 expression is a property of claudin-low cells and tumors and correlates with markers of EMT and breast cancer stem cells. Knockdown of GLI1 expression in claudin-low cell lines resulted in reduced cell viability, motility, clonogenicity, self-renewal, and reduced tumor growth of orthotopic xenografts. We observed non-canonical activation of GLI1 in claudin-low and EMT cell lines, and identified crosstalk with the NFκB pathway. CONCLUSIONS: This work highlights the importance of GLI1 in the maintenance of characteristics of metastatic breast cancer stem cells. Remarkably, treatment with an inhibitor of the NFκB pathway reproducibly reduces GLI1 expression and protein levels. We further provide direct evidence for the binding of the NFκB subunit p65 to the GLI1 promoter in both EMT and claudin-low cell lines. Our results uncover crosstalk between NFκB and GLI1 signals and suggest that targeting these pathways may be effective against the claudin-low breast cancer subtype.

Integrating Emotion Perception in Rehabilitation Programs for Cochlear Implant Users: A Call for a More Comprehensive Approach.

PURPOSE: Postoperative rehabilitation programs for cochlear implant (CI) recipients primarily emphasize enhancing speech perception. However, effective communication in everyday social interactions necessitates consideration of diverse verbal social cues to facilitate language comprehension. Failure to discern emotional expressions may lead to maladjusted social behavior, underscoring the importance of integrating social cues perception into rehabilitation initiatives to enhance CI users' well-being. After conventional rehabilitation, CI users demonstrate varying levels of emotion perception abilities. This disparity notably impacts young CI users, whose emotion perception deficit can extend to social functioning, encompassing coping strategies and social competence, even when relying on nonauditory cues such as facial expressions. Knowing that emotion perception abilities generally decrease with age, acknowledging emotion perception impairments in aging CI users is crucial, especially since a direct correlation between quality-of-life scores and vocal emotion recognition abilities has been observed in adult CI users. After briefly reviewing the scope of CI rehabilitation programs and summarizing the mounting evidence on CI users' emotion perception deficits and their impact, we will present our recommendations for embedding emotional training as part of enriched and standardized evaluation/rehabilitation programs that can improve CI users' social integration and quality of life. CONCLUSIONS: Evaluating all aspects, including emotion perception, in CI rehabilitation programs is crucial because it ensures a comprehensive approach that enhances speech comprehension and the emotional dimension of communication, potentially improving CI users' social interaction and overall well-being. The development of emotion perception training holds promises for CI users and individuals grappling with various forms of hearing loss and sensory deficits. Ultimately, adopting such a comprehensive approach has the potential to significantly elevate the overall quality of life for a broad spectrum of patients.

Incidence and Risk Factors of Systemic Adverse Effects and Complications of Ultrasound- and Fluoroscopy-Guided Glucocorticoid Injections: A Retrospective Cohort Study.

OBJECTIVES: The aims of the study are to assess the incidence of systemic adverse effects and complications of ultrasound-guided and fluoroscopy-guided glucocorticoid injections and to identify associated risk factors. DESIGN: This retrospective cohort study compared participants who received a glucocorticoid injection at the outpatient clinic and participants who had an appointment but did not receive a glucocorticoid injection. Participants were called to verify whether they had experienced any of the predetermined systemic adverse effects and complications. Multiple binary logistic regression was used to identify systemic adverse effect and complication risk factors. RESULTS: There were 1010 participants in the glucocorticoid injection group and 328 in the nonglucocorticoid injection group. There was no statistically significant difference in the occurrence of systemic infection and decompensated heart failure between the two groups. More participants in the glucocorticoid injection group developed abnormal uterine bleeding and erectile dysfunction, but the differences did not reach statistical significance. Female participants were 1.9 times more likely to develop systemic adverse effects ( P < 0.001). Younger age ( P < 0.001), diabetes ( P = 0.012), and higher glucocorticoid injection doses ( P = 0.024) were also associated with an increased risk of developing systemic adverse effects. CONCLUSIONS: Identified risk factors for developing glucocorticoid injection systemic adverse effects were younger age, female sex, diabetes, tobacco use, and high glucocorticoid injection doses.

TRISCEND II: Novel Randomized Trial Design for Transcatheter Tricuspid Valve Replacement.

Severe tricuspid regurgitation remains largely undertreated given limited treatment options. Transcatheter tricuspid valve interventions have emerged as a promising therapy for these patients, and the TRISCEND II pivotal trial is the first randomized controlled trial to evaluate transcatheter tricuspid valve replacement (TTVR). The TRISCEND II pivotal trial studies the transcatheter EVOQUE (Edwards Lifesciences, Irvine, California) tricuspid valve replacement system using a United States Food and Drug Administration Breakthrough Device Designation-a program intended to provide timely access to medical devices by speeding up development, assessment, and review. The TRISCEND II trial is a prospective, multicenter trial that randomizes patients with symptomatic severe tricuspid regurgitation to treatment with either TTVR in conjunction with optimal medical therapy or optimal medical therapy alone. The trial's novel 2-phase design evaluates 30-day safety and 6-month effectiveness end points for the first 150 patients in the initial phase and a 1-year safety and effectiveness end point for the full cohort of 400 patients in the second phase. The TRISCEND II trial's 2-phase trial design provided an opportunity for early review and led to the first commercial approval of a TTVR system. In conclusion, the design of the TRISCEND II trial will likely inform future transcatheter tricuspid device trials.

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors. SIGNIFICANCE: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188.

Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.