Cancer heterogeneity and plasticity最新文献

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, THBS1, 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 THBS1 by siRNA-knockdown induced resistance to enzalutamide. While THBS1 has previously been implicated in aggressive PC phenotypes, we now show that THBS1 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 THBS1 as a potential driver of acute resistance in prostate cancer.

Antibody drug conjugates (ADCs) are changing the landscape of cancer therapy. These agents contain an antibody directed at a tumor cell surface antigen linked to a cytotoxic payload that is released following complex internalization and processing by the lysosome. To date, seven ADCs have been approved by the Federal Drug Administration for the treatment of solid tumors and an additional seven ADCs are approved in hematologic malignancies; because of the unique aspects of solid tumor therapy, this review will focus specifically on ADCs for solid malignancies. Review of the design of these solid tumor ADCs highlights the successful evolution of ADC treatment to date, including selection of antigen target, chemical linker features, and payload. In this review, we focus on how spatial and temporal intratumoral heterogeneity uniquely limits durable efficacy of ADC therapy. We consider strategies to overcome these hurdles, including improved characterization of clinical samples for optimal ADC selection, improvements in ADC design, and combinatorial therapy. These preclinical and clinical efforts seek to overcome the challenges of tumor heterogeneity to improve ADC options and outcomes in the treatment of solid tumor malignancies.

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.

The inaugural FASEB Science Research Conference (SRC) on Cellular Plasticity in Cancer was held in May 2025 in Hong Kong SAR, China. This event brought together leading experts to discuss cutting-edge research centered on cancer cell plasticity. The conference featured comprehensive presentations covering a broad spectrum of topics, including oncofetal reprogramming in tumor development and progression, mechanisms regulating cancer cell plasticity, metabolic reprogramming and its role in tumor progression, cancer cell plasticity during metastasis, cancer stem cell programs within the tumor microenvironment, tumor plasticity and immune evasion, as well as innovative therapeutic strategies aimed at targeting stem cell-like states, modulating cancer cell states, and effectively controlling disease progression. It is anticipated that the insights gained from this meeting will catalyze further advancements in cancer biology and therapy.

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 TERT 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.

Tumor cells that enter senescence as a response to treatment can be permanently arrested or removed by the immune system, resulting in a favorable patient outcomes. Alternatively, many studies have now shown that, in some tumors, the senescent program enables tumor cell survival, persistence, and eventually relapse, resulting in poor patient outcomes. Whether senescence is a positive or negative factor is dependent on whether on a clonal population of cells overcomes three critical barriers. First, senescence must enable survival from the initial stress of treatment, such as DNA damage, by preventing apoptosis and/or mitotic catastrophe. Senescent cells are also frequently immunogenic, thus, a second barrier is the activation of programs of immune evasion, such as PD-L1 expression, that outweigh the immunogenic properties. Third, senescent cells must escape their rigid arrest to proliferate again. Studies over the years have experimentally addressed challenging questions related to relapse and senescence, but more research is needed, particularly in vivo. Here, we discuss critical studies investigating how tumor cells that enter senescence as a response to treatment overcome barriers to relapse.

Breast cancer (BC) is the most common type of cancer among females, and the number of deaths due to BC has increased over the past few decades. BC is primarily categorized based on the receptor status of BC cells as hormone receptor-positive (HR+), human epidermal growth factor receptor 2-positive (HER2+), and triple-negative BC (TNBC). These subtypes differ significantly in their treatment strategies, prognosis, immunogenic nature, and response to immunotherapy. TNBC is the most aggressive with a poor prognosis, but a subset of TNBCs that express programmed cell death ligand 1, have shown promising responses to immune checkpoint inhibitors. Across BC subtypes, distinct immune cell subsets remain active in the tumor immune microenvironment (TIME) that either inhibit or promote the growth of cancer. In isolation, it is challenging for cancer cells to thrive in presence of the body's immune system, however with the aid of other cells in the TIME, they can work together to evade immune detection by suppressing antigen presentation, modulating immune recognition markers, and recruiting immune-suppressive cells. In this review, we provide an overview of the BC immune evasion mechanisms and discuss aspects of immune evasion in relation to tumor heterogeneity and cellular plasticity. We also highlight successful clinical trials targeting immune-evasion markers and discuss the challenges and potential future directions for solving these problems.

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.

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.