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BioRxiv : the Preprint Server For... Jun 2024Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the...
Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from AT2 cells . To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of AT1 and AT2-derived LUAD using KRAS oncogenic driver mouse models. Myeloid cells within the AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the AT2 LUAD TIME was enriched for Arginase-1 myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.
PubMed: 38948812
DOI: 10.1101/2024.06.19.599651 -
BioRxiv : the Preprint Server For... Jun 2024Annotation of the -regulatory elements that drive transcriptional dysregulation in cancer cells is critical to improving our understanding of tumor biology. Herein, we...
Annotation of the -regulatory elements that drive transcriptional dysregulation in cancer cells is critical to improving our understanding of tumor biology. Herein, we present a compendium of matched chromatin accessibility (scATAC-seq) and transcriptome (scRNA-seq) profiles at single-cell resolution from human breast tumors and healthy mammary tissues processed immediately following surgical resection. We identify the most likely cell-of-origin for luminal breast tumors and basal breast tumors and then introduce a novel methodology that implements linear mixed-effects models to systematically quantify associations between regions of chromatin accessibility (i.e. regulatory elements) and gene expression in malignant cells versus normal mammary epithelial cells. These data unveil regulatory elements with that switch from silencers of gene expression in normal cells to enhancers of gene expression in cancer cells, leading to the upregulation of clinically relevant oncogenes. To translate the utility of this dataset into tractable models, we generated matched scATAC-seq and scRNA-seq profiles for breast cancer cell lines, revealing, for each subtype, a conserved oncogenic gene expression program between and cells. Together, this work highlights the importance of non-coding regulatory mechanisms that underlie oncogenic processes and the ability of single-cell multi-omics to define the regulatory logic of BC cells at single-cell resolution.
PubMed: 38948758
DOI: 10.1101/2024.06.13.598858 -
Diseases & Research 2024Cancer leads to nearly 10 million deaths worldwide per year. The tumour microenvironment (TME) is fundamental for tumour growth and progression. A key component of the...
Cancer leads to nearly 10 million deaths worldwide per year. The tumour microenvironment (TME) is fundamental for tumour growth and progression. A key component of the TME, the extracellular matrix (ECM) has recently become a focus of interest in cancer research. Dysregulation of ECM synthesis and proteolysis leads to uncontrolled tumour growth and metastasis. Matrix remodelling enzymes, secreted by cancer cells and stromal cells, modify the overall structure and organisation of ECM proteins, therefore influencing biochemical interactions, tissue integrity and tissue turnover. While A Disintegrin and Metalloproteinases (ADAMs)' and matrix metalloproteinases' role in cancer has been deeply investigated, other proteolytic enzymes, like ADAMs with thrombospondin(-like) motifs (ADAMTSs) have been gaining interest due to their roles in modulating cancer cell-ECM interactions and oncogenic signalling pathways. In this review, we will discuss the dysregulation of ADAMTSs in cancer and their roles in regulating cancer development and progression, via ECM remodelling and cell signalling modulation.
PubMed: 38948119
DOI: 10.54457/DR.202401004 -
Theranostics 2024Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive... (Review)
Review
Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive therapeutic target. In the past decade, the rapid development of various Trop2-targeted therapies, notably marked by the advent of the antibody-drug conjugate (ADC), revolutionized the outcome for patients facing Trop2-positive tumors with limited treatment opinions, such as triple-negative breast cancer (TNBC). This review provides a comprehensive summary of advances in Trop2-targeted therapies, including ADCs, antibodies, multispecific agents, immunotherapy, cancer vaccines, and small molecular inhibitors, along with in-depth discussions on their designs, mechanisms of action (MOAs), and limitations. Additionally, we emphasize the clinical research progress of these emerging Trop2-targeted agents, focusing on their clinical application and therapeutic efficacy against tumors. Furthermore, we propose directions for future research, such as enhancing our understanding of Trop2's structure and biology, exploring the best combination strategies, and tailoring precision treatment based on Trop2 testing methodologies.
PubMed: 38948057
DOI: 10.7150/thno.98178 -
Theranostics 2024Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression. It is of great clinical implications to develop an individualized risk prognostication...
Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression. It is of great clinical implications to develop an individualized risk prognostication approach with stratification-guided therapeutic options for NB based on elucidating molecular mechanisms of metabolic reprogramming. With a machine learning-based multi-step program, the synergic mechanisms of metabolic reprogramming-driven malignant progression of NB were elucidated at single-cell and metabolite flux dimensions. Subsequently, a promising metabolic reprogramming-associated prognostic signature (MPS) and individualized therapeutic approaches based on MPS-stratification were developed and further validated independently using pre-clinical models. MPS-identified MPS-I NB showed significantly higher activity of metabolic reprogramming than MPS-II counterparts. MPS demonstrated improved accuracy compared to current clinical characteristics [AUC: 0.915 vs. 0.657 (), 0.713 (INSS-stage), and 0.808 (INRG-stratification)] in predicting prognosis. AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. Subsequent biological tests revealed AZD7762 substantially inhibited growth, migration, and invasion of MPS-I NB cells, more effectively than that of MPS-II cells. Conversely, etoposide had better therapeutic effects on MPS-II NB cells. More encouragingly, AZD7762 and etoposide significantly inhibited in-vivo subcutaneous tumorigenesis, proliferation, and pulmonary metastasis in MPS-I and MPS-II samples, respectively; thereby prolonging survival of tumor-bearing mice. Mechanistically, AZD7762 and etoposide-induced apoptosis of the MPS-I and MPS-II cells, respectively, through mitochondria-dependent pathways; and MPS-I NB resisted etoposide-induced apoptosis by addiction of glutamate metabolism and acetyl coenzyme A. MPS-I NB progression was fueled by multiple metabolic reprogramming-driven factors including multidrug resistance, immunosuppressive and tumor-promoting inflammatory microenvironments. Immunologically, MPS-I NB suppressed immune cells via and signaling pathways. Metabolically, the malignant proliferation of MPS-I NB cells was remarkably supported by reprogrammed glutamate metabolism, tricarboxylic acid cycle, urea cycle, etc. Furthermore, MPS-I NB cells manifested a distinct tumor-promoting developmental lineage and self-communication patterns, as evidenced by enhanced oncogenic signaling pathways activated with development and self-communications. This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB.
PubMed: 38948053
DOI: 10.7150/thno.93962 -
Oncology Research 2024Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated...
BACKGROUND
Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated with tumorigenesis. is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer. However, the mechanism underlying its function in cancer progression remains poorly understood.
METHODS
Here, the regulatory role of in lung adenocarcinoma was examined using lung cancer cell lines, clinical samples, and xenografts.
RESULTS
We found that high levels of expression were associated with shorter overall survival rate of patients, whereas knockdown of inhibited proliferation of cancer cell lines and tumor growth in xenografts. Western blot and flow cytometry analyses indicated that silencing of induced autophagy and apoptosis. Moreover, we showed that interacted with and stabilized the transcriptional co-repressor Switch-independent 3a (SIN3A), which is a scaffold protein functioning either as a tumor repressor or as an oncogene in a context-dependent manner. Silencing of SIN3A also reduced proliferation of lung cancer cells, which was correlated with the induction of autophagy. These observations raise the possibility that functions to promote the oncogenic activity of SIN3A in lung adenocarcinoma.
CONCLUSIONS
Our findings thus identify SIN3A as a -associated protein and should help to understand the mechanism underlying -mediated oncogenesis.
PubMed: 38948024
DOI: 10.32604/or.2023.030771 -
IScience Jun 2024The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory...
The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory mechanisms in relation to cervical cancer remain insufficiently understood. Through bioinformatics analysis, we revealed that ESM1 was highly expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and correlated with dismal clinicopathological features. The activation of ESM1 is facilitated by the presence of oncogenic HPV E6 and E7. HPV E6 and E7 enhance the expression of ESM1 by diminishing the levels of miR-205-5p, which specifically targets the 3' untranslated region of ESM1 mRNA. In addition, we demonstrated that ESM1 facilitates aerobic glycolysis of cervical cancer cells via the Akt/mTOR pathway. Suppression of ESM1 led to a reduction in the expression of HIF-1α and multiple glycolytic enzymes. Taken together, our findings provide insights into the mechanisms by which HPV infections regulate oncogenes, thereby contributing to cervical carcinogenesis.
PubMed: 38947495
DOI: 10.1016/j.isci.2024.110112 -
Journal of Cancer 2024While RACGAP1 is identified as a potential oncogene, its specific role in lung adenocarcinoma (LUAD) remains unclear. First, we conducted a comprehensive analysis of...
While RACGAP1 is identified as a potential oncogene, its specific role in lung adenocarcinoma (LUAD) remains unclear. First, we conducted a comprehensive analysis of the role of RACGAP1 across 33 types of cancer. Subsequently, we investigated the expression levels of RACGAP1 and its impact on prognosis using data from The Cancer Genome Atlas (TCGA) database. We utilized single-cell sequencing data to explore the tumor-related processes of RACGAP1 in LUAD and validated our findings through experimental verification. Employing a consensus clustering (CC) approach, we subdivided LUAD patients into two subtypes based on RACGAP1 cell cycle-related genes (RrCCGs). These subtypes exhibited significant differences in tumor characteristics, lymph node metastasis, and recurrence. Furthermore, we evaluated the prognostic influence of RrCCGs using univariate Cox regression and least absolute shrinkage and selection operator regression models (LASSO), successfully establishing a prognostic model. RACGAP1 is frequently overexpressed in various tumors and can impact the prognosis of patients with LUAD. Additionally, experimental evidence has demonstrated that low expression of RACGAP1 favors tumor cell apoptosis and restoration of the cell cycle, while high expression promotes invasion and metastasis. Through CC analysis of RrCCGs, patients were classified into two groups, with survival analysis revealing distinct prognoses and stages between the two groups. Furthermore, Cox and LASSO regression successfully constructed a prognostic model with robust predictive capability.
PubMed: 38947404
DOI: 10.7150/jca.96334 -
Journal of Cancer 2024In the realm of cancer research, particularly hepatocellular carcinoma (HCC), TAR DNA-binding protein (TARDBP) has transitioned from being associated with...
In the realm of cancer research, particularly hepatocellular carcinoma (HCC), TAR DNA-binding protein (TARDBP) has transitioned from being associated with neurodegenerative diseases to emerging as a significant molecule in oncology due to its aberrant expression in HCC and other malignancies. This shift underlines the versatility of TARDBP and its critical role in tumorigenesis. Our study illuminates TARDBP's universal upregulation across various cancers, indicating its involvement in fundamental oncogenic processes and potential impact on genomic instability. The relationship between TARDBP expression and tumor mutational burden (TMB) across several cancers highlights its influence on a key hallmark of cancer progression. Additionally, TARDBP's interaction with immune and inflammatory factors within the tumor microenvironment, including its association with immune-stimulatory factors and inverse relationship with immune inhibitors, suggests its role in modulating immune evasion. Clinically, TARDBP's aberrant expression correlates with adverse patient outcomes in HCC, making it a promising candidate for therapeutic targeting. The study concludes that TARDBP holds significant potential as a novel therapeutic target in HCC and possibly other malignancies, meriting further exploration to integrate TARDBP-targeted therapies into cancer treatment protocols, thereby advancing the field of precision medicine.
PubMed: 38947395
DOI: 10.7150/jca.96800 -
Journal of Cancer 2024Acute myeloid leukemia (AML) is the leukemia with the worst prognosis, and current knowledge of AML pathogenesis and available therapies for AML remain limited. 40% of...
Acute myeloid leukemia (AML) is the leukemia with the worst prognosis, and current knowledge of AML pathogenesis and available therapies for AML remain limited. 40% of AML patients exhibit elevated nuclear factor kappa B (NF-κB) activity, which provides a compelling rationale for targeting the NF-κB pathway in AML. Guanine nucleotide-binding protein-like 3-like protein (GNL3L) is a recently identified pro-oncogene that promotes NF-κB activation in a variety of malignancies. For the first time, we comprehensively examined GNL3L expression in AML, reporting GNL3L as a poor prognostic factor in three independent AML cohorts. GNL3L enhanced RELA activity, activated NF-κB, promoted AML cell proliferation, resisted apoptosis, and encouraged cytarabine resistance in AML. In conclusion, these data suggest a role for GNL3L in the malignant process of AML and as a promising therapeutic target.
PubMed: 38947394
DOI: 10.7150/jca.95339