Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma DOI Creative Commons
Yifei Cheng,

Xiaofang Chen,

Feng Li

и другие.

Cell Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 28, 2025

Abstract Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) different biological functions extracellular matrix compositions. Using paired single-cell RNA epigenomic sequencing Stereo-seq, fibroblast subsets CAF-FAP CAF-C7, whose enrichment strongly correlated opposing patient prognosis. We discovered functional units, one intratumor inflammatory hub featured by plus CD8_PDCD1 proximity other marginal wound-healing CAF-C7 Macrophage_SPP1 co-localization. Inhibiting combined anti-PD-1 orthotopic HCC models led to improved regression than either monotherapy. Collectively, our findings suggest stroma-targeted strategies based on defined archetypes, raising concept that CAFs change their transcriptional program intercellular crosstalk according context.

Язык: Английский

Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures DOI Creative Commons
Florent Peyraud,

Jean-Philippe Guégan,

Christophe Rey

и другие.

Cell Reports Medicine, Год журнала: 2025, Номер unknown, С. 101934 - 101934

Опубликована: Фев. 1, 2025

Highlights•mTLSs are predictive of response to ICIs in NSCLC•Two CAF subsets within the TME key determinants primary resistance ICIs•FAP+αSMA+ CAFs correlate with inflammatory and exhaustion CD8+ T cells•MYH11+αSMA+ favor an immunosuppressive CD4+ Treg cell infiltrationSummaryEffectiveness immune checkpoint inhibitors (ICIs) non-small lung cancer (NSCLC) has been linked presence mature tertiary lymphoid structures (mTLSs) tumor microenvironment (TME). However, only a subset mTLS-positive NSCLC derives benefit, thus highlighting need unravel ICI determinants. The comprehensive analysis ICI-treated patients (n = 509) from Bergonié Institute Profiling (BIP) study (NCT02534649) reveals that mTLSs correlates improved clinical outcomes, independently programmed death ligand 1 (PD-L1) expression genomic features. Employing spatial transcriptomics alongside multiplex immunofluorescence (mIF), we show two distinct cancer-associated fibroblasts (CAFs) essential factors mediating NSCLC. These associated exclusion, exhaustion, increased regulatory infiltration, underscoring TME. Our highlights pivotal role specific thwarting ICIs, proposing new therapeutic targets enhance immunotherapy efficacy.Graphical abstract

Язык: Английский

Процитировано

3
Extracellular vesicle-circEHD2 promotes the progression of renal cell carcinoma by activating cancer-associated fibroblasts DOI Creative Commons
Tao He, Qiansheng Zhang, Peng Xu

и другие.

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Июль 22, 2023

Abstract Background The encapsulation of circular RNAs (circRNAs) into extracellular vesicles (EVs) enables their involvement in intercellular communication and exerts an influence on the malignant advancement various tumors. However, regulatory role EVs-circRNA renal cell carcinoma (RCC) remains elusive. Methods vitro vivo functional experiments were implemented to measure effects circEHD2 phenotype RCC. EVs-circEHD2 activation fibroblasts was assessed by collagen contraction assay, western blotting, enzyme-linked immunosorbent assay (ELISA). mechanism investigated RNA pull-down immunoprecipitation, chromatin isolation purification, luciferase co-immunoprecipitation assay. Results We demonstrated that upregulated RCC tissues serum EVs patients with metastasis. Silencing inhibited tumor growth vivo. Mechanistic studies indicated FUS -binding protein (FUS) accelerated cyclization circEHD2, then interacts tyrosine 3-monooxygenase/tryptophan 5-monooxygenase eta (YWHAH), which acts as a bridge recruit Yes1-associated transcriptional regulator (YAP) promoter SRY-box transcription factor 9 (SOX9); this results sustained SOX9. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) regulates package EVs, transmits fibroblasts, converting cancer-associated (CAFs). Activated CAFs promote metastasis secreting pro-inflammatory cytokines such IL-6. Furthermore, antisense oligonucleotides (ASOs) targeting exhibited strong inhibition Conclusions circEHD2/YWHAH/YAP/SOX9 signaling pathway accelerates facilitates CAFs. Our suggest may be useful biomarker therapeutic target for

Язык: Английский

Процитировано

30
Click Chemistry Selectively Activates an Auristatin Protodrug with either Intratumoral or Systemic Tumor-Targeting Agents DOI Creative Commons
Jesse M. McFarland, Maša Alečković, George Coricor

и другие.

ACS Central Science, Год журнала: 2023, Номер 9(7), С. 1400 - 1408

Опубликована: Июнь 22, 2023

The Click Activated Protodrugs Against Cancer (CAPAC) platform enables the activation of powerful cancer drugs at tumors. CAPAC utilizes a click chemistry reaction between tetrazine and trans-cyclooctene. activator, linked to tumor-targeting agent, protodrug leads targeted drug. Here, tumor targeting is achieved by intratumoral injection tetrazine-modified hyaluronate (SQL70) or infusion HER2-targeting antigen-binding fragment (SQT01). Monomethyl auristatin E (a cytotoxin hindered in its clinical use severe toxicity) was modified with trans-cyclooctene form SQP22, which reduced cytotoxicity vitro vivo. Treatment SQP22 paired SQL70 demonstrated antitumor effects Karpas 299 RENCA murine models, establishing requirement for activation. SQT01 induced HER2-positive NCI-N87 xenograft model, showing that tumor-targeted could be accomplished via systemic dosing. Observed toxicities were limited, transient myelosuppression moderate body weight loss detected. This study highlights capabilities demonstrating activity two differentiated approaches underscores power precisely control

Язык: Английский

Процитировано

27
Transcription factors in fibroblast plasticity and CAF heterogeneity DOI Creative Commons
Roberta Melchionna, Paola Trono, Anna Di Carlo

и другие.

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Дек. 20, 2023

Abstract In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity identify commonalities across diverse tumors for more effective therapeutic targeting pro-tumoral stromal microenvironment. However, a unified functional categorization CAF subsets remains elusive, posing challenges development targeted therapies in clinical settings. The phenotype arises from complex interplay signals within tumor microenvironment, where transcription factors serve as central mediators various cellular pathways. Recent advances single-cell RNA sequencing technology have emphasized role conversion normal distinct subtypes cancer types. This review provides comprehensive overview specific roles factor networks shaping heterogeneity, plasticity, functionality. Beginning with influence fibroblast homeostasis reprogramming during wound healing fibrosis, it delves into emerging insights regulatory networks. Understanding these mechanisms not only enables precise characterization but also sheds light early processes governing Ultimately, this knowledge may unveil novel targets treatment, addressing existing stromal-targeted therapies.

Язык: Английский

Процитировано

25
Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis DOI Creative Commons
Cong Chen, Jian Liu,

Xia Lin

и другие.

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Апрель 22, 2024

Abstract Cancer-associated fibroblasts (CAFs), the main stromal component of tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms regulated death (RCD) adjacent cells, thus involving proliferation, therapy resistance, immune exclusion. Here, we present a brief introduction to basic knowledge RCD, including apoptosis, autophagy, ferroptosis, pyroptosis. In addition, further summarize different types RCD tumors are mediated by CAFs, as well effects these modes on CAFs. This review will deepen our understanding interactions between might offer novel therapeutic avenues for future treatments.

Язык: Английский

Процитировано

18
Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer DOI Creative Commons
Lucas Onder, Chrysa Papadopoulou, Almut Lütge

и другие.

Cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

Процитировано

18
Conserved immuno‐collagenic subtypes predict response to immune checkpoint blockade DOI Creative Commons
Jie Mei, Yun Cai, Rui Xu

и другие.

Cancer Communications, Год журнала: 2024, Номер 44(5), С. 554 - 575

Опубликована: Март 20, 2024

Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both clinical, underscores pivotal role extracellular matrix (ECM) modulating immune cell infiltration behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics enhance effectiveness therapy.

Язык: Английский

Процитировано

13
Targeting the tumor microenvironment, a new therapeutic approach for prostate cancer DOI
Bangwei Fang, Ying Lu, Xiaomeng Li

и другие.

Prostate Cancer and Prostatic Diseases, Год журнала: 2024, Номер unknown

Опубликована: Апрель 2, 2024

Язык: Английский

Процитировано

13
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment DOI
Douglas Hanahan, Olivier Michielin, Mikaël J. Pittet

и другие.

Nature reviews. Cancer, Год журнала: 2024, Номер unknown

Опубликована: Окт. 24, 2024

Язык: Английский

Процитировано

13
Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion DOI Creative Commons
Ankita Mitra, Anoop Kumar, Nitin Amdare

и другие.

Biology, Год журнала: 2024, Номер 13(5), С. 307 - 307

Опубликована: Апрель 28, 2024

Cancer immune evasion represents a leading hallmark of cancer, posing significant obstacle to the development successful anticancer therapies. However, landscape cancer treatment has significantly evolved, transitioning into era immunotherapy from conventional methods such as surgical resection, radiotherapy, chemotherapy, and targeted drug therapy. Immunotherapy emerged pivotal component in treatment, harnessing body’s system combat offering improved prognostic outcomes for numerous patients. The remarkable success spurred efforts enhance clinical efficacy existing agents strategies. Several immunotherapeutic approaches have received approval treatments, while others are currently preclinical trials. This review explores recent progress unraveling mechanisms evaluates effectiveness diverse strategies, including vaccines, adoptive cell therapy, antibody-based treatments. It encompasses both established treatments those under investigation, providing comprehensive overview through immunological approaches. Additionally, article emphasizes current developments, limitations, challenges immunotherapy. Furthermore, by integrating analyses resistance exploring combination strategies personalized approaches, it offers valuable insights crucial novel

Язык: Английский

Процитировано

12