The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

Zhang, Xiaoyue; Yang, Wendi; Chen, Kehong; Zheng, Taihao; Guo, Zhengjun; Peng, Yinglin; Yang, Zhenzhou

doi:10.21037/atm-21-4946

Cited by 8 publications

(6 citation statements)

References 52 publications

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“…Disintegrin-like and metalloproteinase domains with thrombospondin type 1 motif (ADAMTS)-like proteins are secreted glycoproteins that are part of the ADAMTS superfamily. ADAMTSL4 is one of the most widely studied members, is associated with aggressive tumor phenotypes, and participates in microfibril formation and function ( 36 ). In glioblastoma multiforme (GBM, WHO grade IV), ADAMTSL4 has been reported to make a contribution to predicting survival ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy

et al. 2023

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IntroductionCellular senescence is a hallmark of tumors and has potential for cancer therapy. Cellular senescence of tumor cells plays a role in tumor progression, and patient prognosis is related to the tumor microenvironment (TME). This study aimed to explore the predictive value of senescence-related genes in thyroid cancer (THCA) and their relationship with the TME.MethodsSenescence-related genes were identified from the Molecular Signatures Database and used to conduct consensus clustering across TCGA-THCA. Differentially expressed genes (DEGs) were identified between the clusters used to perform multivariate Cox regression and least absolute shrinkage and selection operator regression (LASSO) analyses to construct a senescence-related signature. TCGA dataset was randomly divided into training and test datasets to verify the prognostic ability of the signature. Subsequently, the immune cell infiltration pattern, immunotherapy response, and drug sensitivity of the two subtypes were analyzed. Finally, the expression of signature genes was detected across TCGA-THCA and GSE33630 datasets, and further validated by RT-qPCR.ResultsThree senescence clusters were identified based on the expression of 432 senescence-related genes. Then, 23 prognostic DEGs were identified in TCGA dataset. The signature, composed of six genes, showed a significant relationship with survival, immune cell infiltration, clinical characteristics, immune checkpoints, immunotherapy response, and drug sensitivity. Low-risk THCA shows a better prognosis and higher immunotherapy response than high-risk THCA. A nomogram with perfect stability constructed using signature and clinical characteristics can predict the survival of each patient. The validation part demonstrated that ADAMTSL4, DOCK6, FAM111B, and SEMA6B were expressed at higher levels in the tumor tissue, whereas lower expression of MRPS10 and PSMB7 was observed.DiscussionIn conclusion, the senescence-related signature is a promising biomarker for predicting the outcome of THCA and has the potential to guide immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy

et al. 2023

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“…In addition, we found upregulation of thrombospondin type1 domain containing 4 ( Thsd4, Adamtsl6 ) in treated Adam2 O/E tumors. The expression of THSD4 is associated with ICB sensitivity in a TCGA pan-cancer analysis 80,81 . Significantly downregulated genes in treated Adam2 O/E tumors were associated with adipogenesis and metabolism with gene sets associated with ‘glucose homeostasis’, ‘cellular responses to fatty acid’, ‘metabolic and amino acid biosynthetic processes’, ‘angiotensin maturation’; and molecular functions associated with ‘peptide activity’, ‘neutrothropin binding’ and ‘carboxypeptidase and serine type peptidase activity’ ( Fig.…”

Section: Resultsmentioning

confidence: 99%

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

Dervovic

Chen

Malik

et al. 2022

Preprint

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How the genetic landscape of a tumor governs the tumor's response to immunotherapy remains largely elusive. Here, we established a direct in vivo CRISPR/Cas9 gene editing methodology to assess the immune-modulatory capabilities of 573 putative cancer genes associated with altered cytotoxic activity in human cancers. Using KrasG12D- and BrafV600E-driven mouse lung cancer models, we identify Serpinb9 and Adam2 as our top immune suppressive and immune enhancing genes, respectively. Mechanistically, we show that Serpinb9 ablation in KrasG12D- and BrafV600E-mutant lung tumor cells greatly enhances the efficacy of cytotoxic T-cells in vitro and in vivo. ADAM2 is a cancer testis antigen broadly expressed in human cancers such as lung adenocarcinoma (13.9%), renal (74.7%), prostate (72.4%), uterine (28.6%) and invasive breast (9.5%) cancer. In our mouse models, we show that Adam2 expression is induced in KrasG12D- but not BrafV600E-driven murine lung tumors and that its expression is further enhanced by immunotherapy. We show that loss of Adam2 significantly decreases KrasG12D-lung tumor burden but blocks the efficacy of cytotoxic T-cells. Consistently, Adam2 overexpression dramatically increases tumor growth and enhances immunotherapy efficacy. Mechanistically, we find that Adam2's oncogenic function depends on modulating the tumor immune microenvironment by restraining productive type I and type II interferon responses as well as cytokine signaling, reducing the presentation of tumor-associated antigen, and modulating surface expression of several immunoregulatory receptors within Kras-driven lung tumors. Adam2 expression also leads to reduced levels of immune checkpoint inhibitors such as Pd-l1, Lag3, Tigit and Tim3. This reduced exhaustion within the tumor microenvironment may explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy against Adam2 overexpressing lung tumors. Together, our study highlights the power of integrating cancer genomic with in vivo CRISPR/Cas9 screens to uncover how cancer-associated genetic alterations control responses to immunotherapies.

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“…These ndings may be generally applicable across cancer types, because metabolic syndrome is associated with increased risk of multiple common human cancers (1), and because the direct risk elements of cancer initiation and promotion are believed to underlie cancer risk in all organ sites (17,18). Nonetheless, other mechanisms speci c to only certain cancer types may also exist.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer promotion is mediated by cell hyperproliferation, resulting from exposures inducing abnormally rapid cell proliferation, which provides su cient cell generations for somatic cellular evolution to occur on a relevant time scale (13,15,16). The two biological processes of cancer initiation and promotion are believed to underlie cancer risk for all organ sites (17,18).…”

Section: Methodsmentioning

confidence: 99%

Integrated Analysis of Cancer Risk from Metabolic Dysfunction: Biological Mechanisms and Tipping Points

Pepper

2023

Preprint

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Obesity and metabolic syndrome are associated with the incidence of cancer, and they are rising epidemics. Therefore, clarification of the biological mechanisms of metabolic cancer risk is needed to guide strategies to intercept any elevated cancer risk resulting from metabolic syndrome. This study addressed whether interactions among known biological mechanisms elevate cancer risk, and which mechanisms offer the best leverage points for preventing any resulting cancer risk. It used a systems approach to examine the network of biological mechanisms, with special attention to clinically important feedbacks and tipping points. The results show that while no single mechanism leads from metabolic dysfunction to cancer risk, the integrated network of known mechanisms does. Metabolic syndrome collectively, and most of its components individually, induce documented oncogenic pathways. A network of such pathways leads from metabolic dysfunction to oncogenesis. This network includes self-reinforcing feedback loops, mostly centered on systemic metabolic inflammation, that can create tipping points into chronically dysfunctional metabolism with elevated cancer risk. Optimal interventions to reduce cancer risk should preempt these tipping points by targeting elements of metabolic dysfunction upstream of known feedback loops.

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The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

Cited by 8 publications

References 52 publications

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

Integrated Analysis of Cancer Risk from Metabolic Dysfunction: Biological Mechanisms and Tipping Points

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