Disruption of Y chromosome expression in male lung cancer: discovery
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151101 | GEO | 2021/06/15
REPOSITORIES: GEO
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Project description:Lung cancer is the single most frequent cause of cancer death worldwide and is relatively more common in males. For reasons that are currently unknown, lung cancer is also associated with significantly worse outcomes in men than women. Here we replicate clustering of Y-chromosome transcripts identified previously as showing tumor-specific disruption in men with lung cancer.
2021-06-15 | GSE151102 | GEO
Project description:Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, refractory tumors with compound mutations or diverse resistance mechanisms remain an unmet clinical need. In this study, we established mouse tumor-derived cell models representing the most common EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles. We demonstrated that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, which is frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects on both ALK-driven murine tumor growth and ALK-patient-derived cells. This death mechanism is attributed to the profound perturbation of the (phospho)proteomic landscape, together with a synergistic suppressive effect on the mTOR pathway. Taken together, our study identifies the inhibition of ALK and SRC cells and may offer a promising strategy to overcome resistance mechanisms and improve clinical outcomes in ALK-positive lung cancer patients.
2024-04-11 | PXD043012 | Pride
Project description:Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, refractory tumors with compound mutations or diverse resistance mechanisms remain an unmet clinical need. In this study, we established mouse tumor-derived cell models representing the most common EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles. We demonstrated that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, which is frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects on both ALK-driven murine tumor growth and ALK-patient-derived cells. This death mechanism is attributed to the profound perturbation of the (phospho)proteomic landscape, together with a synergistic suppressive effect on the mTOR pathway. Taken together, our study identifies the inhibition of ALK and SRC cells and may offer a promising strategy to overcome resistance mechanisms and improve clinical outcomes in ALK-positive lung cancer patients.
2024-04-11 | PXD042728 | Pride
Project description:Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1500 Da) were measured in urine collected from 469 lung cancer patients and 536 population controls using unbiased liquid chromatography-mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further validated in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared to the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA), were each significantly (P <0.00001) elevated in non–small cell lung cancer (NSCLC) and associated with worse prognosis (hazard ratio (HR) =1.81 [P =0.0002], and 1.54 [P =0.025], respectively). Creatine riboside was the strongest classifier of lung cancer status in all and stage I–II cases, important for early detection, and also associated with worse prognosis in stage I–II lung cancer (HR =1.71, P =0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 – 0.99. Both metabolites were significantly (P <0.03) enriched in tumor tissue compared to adjacent non-tumor tissue (N =48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.
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Project description:Mounting evidence points to a link between a cancer possessing stem-like properties and a worse prognosis. To understand the biology, a common approach is to integrate network biology with signal processing mechanics. That said, even with the right tools, predicting the risk for a highly susceptible target using only a handful of gene signatures remains very difficult. By compiling the expression profiles of a panel of tumor stem-like cells (TSLCs) originating in different tissues, comparing these to their parental tumor cells (PTCs) and the human embryonic stem cells (hESCs), and integrating network analysis with signaling mechanics, we propose that network topologically-weighted signaling processing measurements under tissue-specific conditions can provide scalable and predicable target identification. All function codes related to this project could be accessed at the supplementary website. We hypothesized that the transcriptional stochastic element of lung tumors modeled by the lung-TSLC networks could be utilized to estimate the prognostic survival times. A scalable, network-based signal-processing model was devised to analyze the transcriptional signal for a single gene or for a set of genes relating to other gene players in the networks. We tested our hypothesis in the following three steps: (1) construct the consensus TSLC networks and the lung-TSLC networks by analyzing the transcriptomes of three panels of cells: the parental tumor cells (PTCs), the cultivated TSLCs, and the human embryonic stem cels (hESCs); (2) develop network topologically-weighted signal processing measurements and apply such measurements to find the survival correlation and to identify potential targets for biological validation; and (3) verify a potential regulatory target - Cbx5 - in another clinical cohort of LACs as well as in knock-down experiments in lung TSLCs functional assays and in animal models.
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Project description:Ctcf heterozygous knockout mice are susceptible to neoplasia in a broad range of tissues, including lymphoma, endometrial cancer, and non-small cell lung cancer. Retention of the wild type Ctcf allele in these tumors establishes CTCF as a haploinsufficient tumor suppressor gene. Both human tumors and normal murine tissues with CTCF disruption are characterized by genome-wide differences in DNA methylation relative to CTCF wild type tissues, indicating even modest disruption of CTCF broadly destabilizes DNA methylation in vivo. This cross species functional analysis identifies CTCF as a commonly mutated tumor suppressor gene and establishes a central role for DNA methylation stability in tumor suppression. RRBS sequencing of transgenic Ctcf heterozygous mice and wild-type litter mate whole lung tissue.
2014-07-30 | E-GEOD-48975 | biostudies-arrayexpress
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
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