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Nature Jun 2019Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of...
Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
Topics: Case-Control Studies; Circulating Tumor DNA; Cohort Studies; DNA Fragmentation; DNA Mutational Analysis; Genome, Human; Humans; Machine Learning; Mutation; Neoplasms
PubMed: 31142840
DOI: 10.1038/s41586-019-1272-6 -
Journal of Hematology & Oncology Jan 2020Patient-derived tumor xenografts (PDXs), in which tumor fragments surgically dissected from cancer patients are directly transplanted into immunodeficient mice, have... (Review)
Review
Patient-derived tumor xenografts (PDXs), in which tumor fragments surgically dissected from cancer patients are directly transplanted into immunodeficient mice, have emerged as a useful model for translational research aimed at facilitating precision medicine. PDX susceptibility to anti-cancer drugs is closely correlated with clinical data in patients, from whom PDX models have been derived. Accumulating evidence suggests that PDX models are highly effective in predicting the efficacy of both conventional and novel anti-cancer therapeutics. This also allows "co-clinical trials," in which pre-clinical investigations in vivo and clinical trials could be performed in parallel or sequentially to assess drug efficacy in patients and PDXs. However, tumor heterogeneity present in PDX models and in the original tumor samples constitutes an obstacle for application of PDX models. Moreover, human stromal cells originally present in tumors dissected from patients are gradually replaced by host stromal cells as the xenograft grows. This replacement by murine stroma could preclude analysis of human tumor-stroma interactions, as some mouse stromal cytokines might not affect human carcinoma cells in PDX models. The present review highlights the biological and clinical significance of PDX models and three-dimensional patient-derived tumor organoid cultures of several kinds of solid tumors, such as those of the colon, pancreas, brain, breast, lung, skin, and ovary.
Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Humans; Neoplasms; Organ Culture Techniques; Organoids; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 31910904
DOI: 10.1186/s13045-019-0829-z -
Nature Medicine Aug 2015Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult...
Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult to analyze systematically. Here we present a pan-cancer resource and meta-analysis of expression signatures from ∼18,000 human tumors with overall survival outcomes across 39 malignancies. By using this resource, we identified a forkhead box MI (FOXM1) regulatory network as a major predictor of adverse outcomes, and we found that expression of favorably prognostic genes, including KLRB1 (encoding CD161), largely reflect tumor-associated leukocytes. By applying CIBERSORT, a computational approach for inferring leukocyte representation in bulk tumor transcriptomes, we identified complex associations between 22 distinct leukocyte subsets and cancer survival. For example, tumor-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. This resource and associated analytical tools (http://precog.stanford.edu) may help delineate prognostic genes and leukocyte subsets within and across cancers, shed light on the impact of tumor heterogeneity on cancer outcomes, and facilitate the discovery of biomarkers and therapeutic targets.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Neoplasms; Neutrophil Infiltration; Plasma Cells; Prognosis
PubMed: 26193342
DOI: 10.1038/nm.3909 -
Nature Mar 2020Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis). Gasdermin E (GSDME, also known as...
Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis). Gasdermin E (GSDME, also known as DFNA5)-mutated in familial ageing-related hearing loss-can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer, suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8 T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity.
Topics: Animals; Apoptosis; Aspartic Acid; Cell Line, Tumor; Female; Granzymes; Humans; Loss of Function Mutation; Mice; Neoplasms; Pyroptosis; Receptors, Estrogen; T-Lymphocytes, Cytotoxic
PubMed: 32188940
DOI: 10.1038/s41586-020-2071-9 -
Nature Communications Jun 2022Mitochondria generate ATP and play regulatory roles in various cellular activities. Cancer cells often exhibit fragmented mitochondria. However, the underlying mechanism...
Mitochondria generate ATP and play regulatory roles in various cellular activities. Cancer cells often exhibit fragmented mitochondria. However, the underlying mechanism remains elusive. Here we report that a mitochondrial protein FUN14 domain containing 2 (FUNDC2) is transcriptionally upregulated in primary mouse liver tumors, and in approximately 40% of human hepatocellular carcinoma (HCC). Importantly, elevated FUNDC2 expression inversely correlates with patient survival, and its knockdown inhibits liver tumorigenesis in mice. Mechanistically, the amino-terminal region of FUNDC2 interacts with the GTPase domain of mitofusin 1 (MFN1), thus inhibits its activity in promoting fusion of outer mitochondrial membrane. As a result, loss of FUNDC2 leads to mitochondrial elongation, decreased mitochondrial respiration, and reprogrammed cellular metabolism. These results identified a mechanism of mitochondrial fragmentation in cancer through MFN1 inhibition by FUNDC2, and suggested FUNDC2 as a potential therapeutic target of HCC.
Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; GTP Phosphohydrolases; Humans; Liver Neoplasms; Mice; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins
PubMed: 35710796
DOI: 10.1038/s41467-022-31187-6 -
Genome Research Feb 2022Current evidence suggests that plasma cell-free DNA (cfDNA) is fragmented around a mode of 166 bp. Data supporting this view has been mainly acquired through the...
Current evidence suggests that plasma cell-free DNA (cfDNA) is fragmented around a mode of 166 bp. Data supporting this view has been mainly acquired through the analysis of double-stranded cfDNA. The characteristics and diagnostic potential of single-stranded and damaged double-stranded cfDNA in healthy individuals and cancer patients remain unclear. Here, through a combination of high-affinity magnetic bead-based DNA extraction and single-stranded DNA sequencing library preparation (MB-ssDNA), we report the discovery of a large proportion of cfDNA fragments centered at ∼50 bp. We show that these "ultrashort" cfDNA fragments have a greater relative abundance in plasma of healthy individuals (median = 19.1% of all sequenced cfDNA fragments, = 28) than in plasma of patients with cancer (median = 14.2%, = 21, < 0.0001). The ultrashort cfDNA fragments map to accessible chromatin regions of blood cells, particularly in promoter regions with the potential to adopt G-quadruplex (G4) DNA secondary structures. G4-positive promoter chromatin accessibility is significantly enriched in ultrashort plasma cfDNA fragments from healthy individuals relative to patients with cancers ( < 0.0001), in whom G4-cfDNA enrichment is inversely associated with copy number aberration-inferred tumor fractions. Our findings redraw the landscape of cfDNA fragmentation by identifying and characterizing a novel population of ultrashort plasma cfDNA fragments. Sequencing of MB-ssDNA libraries could facilitate the characterization of gene regulatory regions and DNA secondary structures via liquid biopsy. Our data underline the diagnostic potential of ultrashort cfDNA through classification for cancer patients.
Topics: Biomarkers, Tumor; Cell-Free Nucleic Acids; DNA; DNA, Single-Stranded; Humans; Neoplasms; Sequence Analysis, DNA
PubMed: 34930798
DOI: 10.1101/gr.275691.121 -
Head and Neck Pathology Sep 2018Ceruminous glands are modified apocrine glands located in the external auditory canal (EAC). Neoplastic lesions arising from these glands are rare in humans and... (Review)
Review
Ceruminous glands are modified apocrine glands located in the external auditory canal (EAC). Neoplastic lesions arising from these glands are rare in humans and constitute a major differential diagnosis for glandular neoplasms of the EAC. Due to anatomic restrictions, benign and malignant neoplasms present with similar symptoms and to some extent even comparable radiologic features, particularly when the tumors are localized. Biopsies are frequently limited by small size, fragmentation and improper anatomic and architectural orientation, thereby hampering our ability to appreciate the relationship of peripheral edges of the tumor to the surrounding tissue. Benign and malignant tumors may also have overlapping histomorphologic features, which further magnifies the challenges in accurate diagnosis and management strategies. This article summarizes the salient clinical, radiologic and histologic features of common ceruminous gland tumors, in addition to discussing features that can aid in differentiating ceruminous tumors from other EAC tumors and to distinguish benign from malignant entities.
Topics: Apocrine Glands; Ear Canal; Ear Neoplasms; Humans; Neoplasms, Glandular and Epithelial
PubMed: 30069843
DOI: 10.1007/s12105-018-0909-3 -
Molecular Cancer Jul 2023Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and...
Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N-methylguanosine (mG) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of mG tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed mG tRNA methylation in cancer cell translation control and tumour biology.
Topics: Male; Humans; Carcinogenesis; Cell Transformation, Neoplastic; Prostatic Neoplasms; Transcription, Genetic; RNA Processing, Post-Transcriptional; Methyltransferases
PubMed: 37516825
DOI: 10.1186/s12943-023-01809-8 -
The Journal of Experimental Medicine Jan 2023Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we...
Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
Topics: Humans; Angiopoietin-Like Protein 4; Angiopoietins; Biomarkers, Tumor; Neoplasms; Peptide Fragments
PubMed: 36269299
DOI: 10.1084/jem.20202595 -
Nanomedicine : Nanotechnology, Biology,... Jan 2019Peptide and protein-based cancer vaccines usually fail to elicit efficient immune responses against tumors. However, delivery of these peptides and proteins as... (Review)
Review
Peptide and protein-based cancer vaccines usually fail to elicit efficient immune responses against tumors. However, delivery of these peptides and proteins as components within caged protein nanoparticles has shown promising improvements in vaccine efficacy. Advantages of protein nanoparticles over other vaccine platforms include their highly organized structures and symmetry, biodegradability, ability to be specifically functionalized at three different interfaces (inside and outside the protein cage, and between subunits in macromolecular assembly), and ideal size for vaccine delivery. In this review, we discuss different classes of virus-like particles and caged protein nanoparticles that have been used as vehicles to transport and increase the interaction of cancer vaccine components with the immune system. We review the effectiveness of these protein nanoparticles towards inducing and elevating specific immune responses, which are needed to overcome the low immunogenicity of the tumor microenvironment.
Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Drug Delivery Systems; Humans; Nanoparticles; Neoplasm Proteins; Neoplasms; Peptide Fragments
PubMed: 30291897
DOI: 10.1016/j.nano.2018.09.004