Cancer heterogeneity and plasticity最新文献

{"title":"Combined Transcriptomic and Epitranscriptomic Profiling Identifies THBS1 as A Regulator of Enzalutamide Resistance in Prostate Cancer.","authors":"Emmanuelle Hodara, Lisa Swartz, Aubree Mades, Daniel Bsteh, Tong Xu, Suhn K Rhie, Amir Goldkorn","doi":"10.47248/chp2502020007","DOIUrl":"https://doi.org/10.47248/chp2502020007","url":null,"abstract":"<p><p>Cancer drug resistance arises not only from selection of resistant clones, but also through rapid activation of adaptive transcriptional programs. One mechanism of transcriptional regulation involves N6-methyladenosine (m⁶A) RNA modification, which dynamically regulates mRNA processing and alternative splicing, ultimately impacting cell fate and differentiation. In prostate cancer (PC), resistance to systemic therapies such as the androgen receptor pathway inhibitor (ARPI) enzalutamide is associated with a host of well-documented androgen receptor (AR) alterations, including amplification, mutation, and alternative splicing. Given these functions, we hypothesized that m⁶A modifications play a role in the transition to enzalutamide resistance in PC. To test this, we used methyl-RNA-immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA-seq to identify gene transcripts that were both differentially methylated and differentially expressed between enzalutamide-sensitive and enzalutamide-resistant PC cells. We filtered and prioritized these genes using clinical and functional database tools, including Gene Ontology (GO) enrichment analysis and Gene Set Enrichment Analysis (GSEA), The Cancer Genome Atlas (TCGA), and the Oncology Research Information Network (ORIEN) avatar. Using this approach, we identified 487 transcripts that were both differentially methylated and differentially expressed and validated six of the top 12 candidates via targeted qPCR and MeRIP-PCR. One of these, <i>THBS1</i>, was found to have increased m⁶A level associated with decreased transcript levels in enzalutamide-resistant cells, a finding recapitulated in publicly available preclinical and clinical data. Moreover, in enzalutamide-sensitive cells, depletion of <i>THBS1</i> by siRNA-knockdown induced resistance to enzalutamide. While <i>THBS1</i> has previously been implicated in aggressive PC phenotypes, we now show that <i>THBS1</i> downregulation directly contributes to a rapid transition to enzalutamide resistance, suggesting a novel role for this gene in PC hormonal therapy resistance. These results constitute the first comprehensive epitranscriptomic profiling of ARPI resistance and identify <i>THBS1</i> as a potential driver of acute resistance in prostate cancer.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell Cycle Plasticity and Heterogeneity: An Underappreciated Feature of Cancer and Treatment Response.","authors":"Erik S Knudsen, Thomas N O'Connor, Agnieszka K Witkiewicz","doi":"10.47248/chp2502030015","DOIUrl":"10.47248/chp2502030015","url":null,"abstract":"<p><p>Progression through the mammalian cell cycle is a highly regulated process to maintain tissue homeostasis. The key regulators of cell cycle transitions are cyclin-dependent kinase (CDK)/Cyclin complexes that phosphorylate substrates such as the RB tumor suppressor to facilitate cellular division. The regulation of G1/S is of particular significance in cancer and is affected by numerous tumor suppressors and oncogenes. Historically, the cell cycle was viewed as a rigidly regulated process, but recent evidence has revealed significant flexibility and differential CDK/Cyclin dependencies across tumor types. These heterogeneous features of cell cycle control have implications for the etiology of different tumor types as well as the response to multiple therapeutic modalities. Most notably, adaptive responses in cell cycle regulatory circuits can contribute to acquired resistance in a variety of contexts, underscoring the importance for tumor biology and disease treatment.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12525970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Characteristics, Heterogeneity, Plasticity, and Cell of Origin of Neuroendocrine Bladder Cancer.","authors":"Dongbo Xu, Qiang Li","doi":"10.47248/chp2502010005","DOIUrl":"10.47248/chp2502010005","url":null,"abstract":"<p><p>Neuroendocrine bladder cancer (NEBC) is a rare but highly aggressive cancer, representing approximately 1% of urinary bladder cancer. The most common NEBC is small cell bladder cancer (SCBC), characterized by high rates of recurrence, chemotherapy resistance, and early mortality. SCBC is histologically identical to small cell lung cancer (SCLC) but remains significantly understudied. Advances in next-generation sequencing techniques have partially elucidated the molecular characteristics of NEBC and identified druggable targets. This review compiles recent studies on human NEBC samples, summarizing key findings on their genomic alterations and molecular subtyping. Notably, it highlights specific mutations in the <i>TERT</i> promoter and epigenetic modifiers in NEBC, as well as molecular subtyping based on lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. Furthermore, this review explores the significant tumor heterogeneity and cellular plasticity observed in NEBC and discusses its cell of origin and potential therapeutic targets (MET inhibitor or DLL3) identified by preclinical NEBC models. Emerging evidence suggests that NEBC may share a common origin with urothelial carcinoma (UC), arising from a UC precursor. Advancing our understanding of NEBC tumorigenesis and identifying druggable targets will enhance treatment outcomes for patients with NEBC.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Single-Cell Techniques for Linking Phenotypes to Genotypes.","authors":"Hsiao-Chun Chen, Yushu Ma, Jinxiong Cheng, Yu-Chih Chen","doi":"10.47248/chp2401010004","DOIUrl":"10.47248/chp2401010004","url":null,"abstract":"<p><p>Single-cell analysis has become an essential tool in modern biological research, providing unprecedented insights into cellular behavior and heterogeneity. By examining individual cells, this approach surpasses conventional population-based methods, revealing critical variations in cellular states, responses to environmental cues, and molecular signatures. In the context of cancer, with its diverse cell populations, single-cell analysis is critical for investigating tumor evolution, metastasis, and therapy resistance. Understanding the phenotype-genotype relationship at the single-cell level is crucial for deciphering the molecular mechanisms driving tumor development and progression. This review highlights innovative strategies for selective cell isolation based on desired phenotypes, including robotic aspiration, laser detachment, microraft arrays, optical traps, and droplet-based microfluidic systems. These advanced tools facilitate high-throughput single-cell phenotypic analysis and sorting, enabling the identification and characterization of specific cell subsets, thereby advancing therapeutic innovations in cancer and other diseases.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular determinants of phenotypic plasticity in homeostasis and neoplasia.","authors":"Bradley Balk, David W Goodrich","doi":"10.47248/chp2401020010","DOIUrl":"10.47248/chp2401020010","url":null,"abstract":"<p><p>Phenotypic plasticity, the capacity of cells to transition between distinct phenotypic and lineage states over time, is a genetically and epigenetically encoded trait essential for normal development and adult tissue homeostasis. In cancer, phenotypic plasticity programs can be deployed aberrantly to enable disease progression and acquired therapeutic resistance. Cancer phenotypic plasticity is a current barrier to achieving cures for advanced cancers using available molecularly targeted therapies. This review summarizes the complex and interconnected molecular pathways implicated in phenotypic plasticity, both in the context of normal tissue homeostasis and cancer. Molecular pathways convergent between these contexts are highlighted while pathways enabling plasticity are distinguished from those that specify the phenotype of already plastic cells. Key unresolved questions in the field are discussed along with emerging technologies that may be used to help answer them.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unmasking SMLR1: The hidden player in colorectal cancer's liver metastasis.","authors":"Xiaozhuo Liu","doi":"10.47248/chp2401010002","DOIUrl":"https://doi.org/10.47248/chp2401010002","url":null,"abstract":"","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142336201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Cancer Heterogeneity and Plasticity</i> - A new journal dedicated to understanding cancer cell states and interactions with the tumor microenvironment.","authors":"Dean G Tang","doi":"10.47248/chp2401010001","DOIUrl":"10.47248/chp2401010001","url":null,"abstract":"","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance.","authors":"Anmbreen Jamroze, Xiaozhuo Liu, Dean G Tang","doi":"10.47248/chp2401010005","DOIUrl":"10.47248/chp2401010005","url":null,"abstract":"<p><p>Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states and with distinct phenotypes, functions, and drug sensitivities. This inherent cancer cell heterogeneity contributes to tumor resistance to clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called lineage infidelity) in cancer cells that also drives therapy resistance. In this Perspective, we focus our discussions on cancer cell lineage plasticity manifested as treatment-induced switching of epithelial cancer cells to basal/stem-like, mesenchymal, and neural lineages. We employ prostate cancer (PCa) as the prime example to highlight ARSI-induced lineage plasticity during and towards development of castration-resistant PCa (CRPC). We further discuss how the tumor microenvironment (TME) influences therapy-induced lineage plasticity. Finally, we offer an updated summary on the regulators and mechanisms driving cancer cell lineage infidelity, which should be therapeutically targeted to extend the therapeutic window and improve patients' survival.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}