Individualized Molecular Mechanisms and Treatment in Tumor Metastasis

Topic Information

Dear Colleagues,

The purpose and scope of tumor metastasis are still a challenge for personalized tumor therapy and an important reason for the poor prognosis of tumor patients. In recent years, researchers have attempted to apply genomics, transcriptomic, and proteomic techniques to establish reasonably stable animal tumor metastasis models to explore the internal tumor microenvironment and molecular mechanisms during the process of metastasis and subsequently study the potential drug targets in metastatic tumors. However, even the metastatic process of a specific tumor has individual characteristics. With the progress of research in this field, more and more mechanisms related to the metastatic process have been reported, such as exosomes, the tumor metabolism, etc. Therefore, the complexity of tumor metastasis brings difficulties and challenges, and more advanced research is urgently needed. This Special Collection aims to collect recent advances in the pathogenesis and treatment strategies of metastatic neoplastic processes. Potential submissions include but are not limited to:

• The latest research on the process of tumor metastasis, such as vascular invasion, pre-metastatic niche formation, engraftment of metastases, and resistance to anoikis;
• The latest research on the role of the tumor microenvironment in tumor metastasis, including the interaction of tumor cells and non-tumor cells, spatiotemporal changes of the tumor microenvironment, multi-omics-based exploration of the tumor microenvironment, and drug resistance in metastatic tumors.

Dr. Dong Tang
Dr. Chen Liu
Prof. Dr. Bin Cheng
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	15.3 Days	CHF 2600	Submit
Cancers cancers	4.5	8.0	2009	16.3 Days	CHF 2900	Submit
Current Oncology curroncol	2.8	3.3	1994	17.6 Days	CHF 2200	Submit
Onco onco	-	-	2021	19 Days	CHF 1000	Submit
Pathophysiology pathophysiology	2.7	3.1	1994	22.8 Days	CHF 1400	Submit

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Published Papers (7 papers)

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All Biomedicines Cancers Current Oncology Onco Pathophysiology

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12 pages, 1664 KiB  

Open AccessArticle

Revisiting the Role of PD-L1 Overexpression in Prognosis and Clinicopathological Features in Patients with Oral Squamous Cell Carcinoma

by Fernando Leporace-Jiménez, Isabel Portillo-Hernandez, Justino Jiménez-Almonacid, Ignacio Zubillaga Rodriguez, María Mejía-Nieto, Pablo Caballero Pedrero and Gregorio Sanchez Aniceto

Onco 2024, 4(3), 131-142; https://doi.org/10.3390/onco4030011 - 12 Jul 2024

Viewed by 964

Abstract

Background: PD1 and its ligand PD-L1 are related to prognosis in many solid tumors; however, their role in oral squamous cell carcinoma (OSCC) remains unclear. Methods: A retrospective monocentric study including all patients with OSCC diagnosed and treated between January 2020 and May [...] Read more.

Background: PD1 and its ligand PD-L1 are related to prognosis in many solid tumors; however, their role in oral squamous cell carcinoma (OSCC) remains unclear. Methods: A retrospective monocentric study including all patients with OSCC diagnosed and treated between January 2020 and May 2022 was performed. PD-L1 expression was assessed per a combined positive score (CPS), considering a CPS of > or equal to 1 as positive (1–20 indicating “low expression” and ≥20 indicating “high”). A descriptive analysis of the patient cohort and tumors was performed, including tumor size, stage, lymph node involvement, recurrence, and survival. Results: In total, 65 patients (65 tumors) were analyzed. A total of 66.15% of the tumors were in advanced stages (III-IV), of which 97.67% expressed PD-L1+, compared with 71.42% in the early stages (I–II). T4 tumors expressed PD-L1 in 100% of cases, compared with 54% in T1 tumors. A total of 50.79% of the tumors showed lymph node involvement (pN+), with 100% of the pN+ showing PD-L1+. The prevalence of pN+ was 59.38% vs. 40.63% for high vs. low PD-L1 expression, respectively. Patients’ follow-ups ranged from 2 to 34.5 months. No significant difference was seen between overall survival (OS) and PD-L1 +/− (CPS ≥ 1 vs. CPS < 1) or high (CPS ≥ 20) and low (CPS < 20) PD-L1 expression (p < 0.97 and 0.64, respectively). Conclusions: The method used to measure PD-L1 (a laboratory test with Dako 22C3 anti-PD-L1 primary antibodies) was reliable and accurate, with a correlation coefficient between PD-L1 expression in the biopsy and the surgical piece of 0.83 (p < 0.0001). A CPS of ≥1 was observed in large tumors (p < 0.001) and was correlated with that of lymph node metastases (p < 0.004). Further analysis of PD-L1 expression in OSCC and studies to determine its relevance in tumor biology and prognosis is needed. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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15 pages, 2991 KiB  

Open AccessReview

The World of Immunotherapy Needs More Than PD-1/PD-L1—Two of the New Kids on the Block: LAG-3 and TIGIT

by João Martins Gama, Paulo Teixeira and Rui Caetano Oliveira

Onco 2024, 4(3), 116-130; https://doi.org/10.3390/onco4030010 - 1 Jul 2024

Viewed by 992

Abstract

Immunotherapy has paved the way for the development of solid tumor new treatments in the last decade. The approval of immune checkpoint inhibitors such as anti PD-1/PD-L1 provided a revolution with optimal results. However, a considerable proportion of patients experience adverse therapeutic effects, [...] Read more.

Immunotherapy has paved the way for the development of solid tumor new treatments in the last decade. The approval of immune checkpoint inhibitors such as anti PD-1/PD-L1 provided a revolution with optimal results. However, a considerable proportion of patients experience adverse therapeutic effects, and up to 50% may develop secondary resistance in the first three to five years. This has prompted the need for identifying new targets for immunotherapy that have good tolerance and biosafety and, of course, good tumoral response, either alone or in combination. Two of these new targets are the Lymphocyte-activation gene 3 (LAG-3) and the T cell immunoglobulin and ITIM domain (TIGIT). They are responsible for several interactions with the immune system, prompting an immunosuppressive phenotype in the tumor microenvironment. Both LAG-3 and TIGIT can be druggable, alone or in combination with anti-PD-1/PD-L1, with rather safe profiles making them attractive. In this review, we highlight some of the immune mechanisms of TIGIT and LAG-3 and their detection by immunohistochemistry, providing some insight into their use in the clinical setting. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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18 pages, 5955 KiB  

Open AccessArticle

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

by Ruhi Gulati, Yasmeen Fleifil, Katherine Jennings, Alex Bondoc, Greg Tiao, James Geller, Lubov Timchenko and Nikolai Timchenko

Cancers 2024, 16(13), 2300; https://doi.org/10.3390/cancers16132300 - 22 Jun 2024

Cited by 1 | Viewed by 954

Abstract

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer [...] Read more.

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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14 pages, 2460 KiB  

Open AccessArticle

Patient Derived Xenografts (PDX) Models as an Avatar to Assess Personalized Therapy Options in Uveal Melanoma: A Feasibility Study

by Fariba Nemati, Leanne de Koning, David Gentien, Franck Assayag, Emilie Henry, Khadija Ait Rais, Gaelle Pierron, Odette Mariani, Michèle Nijnikoff, Gabriel Champenois, André Nicolas, Didier Meseure, Sophie Gardrat, Nicolas Servant, Philippe Hupé, Maud Kamal, Christophe Le Tourneau, Sophie Piperno-Neumann, Manuel Rodrigues, Sergio Roman-Roman, Didier Decaudin, Pascale Mariani and Nathalie Cassouxadd Show full author list remove Hide full author list

Curr. Oncol. 2023, 30(10), 9090-9103; https://doi.org/10.3390/curroncol30100657 - 11 Oct 2023

Cited by 2 | Viewed by 2120

Abstract

Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist. Here, we investigated the feasibility of establishing patient-derived [...] Read more.

Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist. Here, we investigated the feasibility of establishing patient-derived xenografts (PDXs) from a patient’s tumor in order to screen for therapies that the patient could benefit from. Samples obtained from 29 primary tumors and liver metastases of uveal melanoma were grafted into SCID mice. PDX models were successfully established for 35% of primary patient tumors and 67% of liver metastases. The tumor take rate was proportional to the risk of metastases. PDXs showed the same morphology, the same GNAQ/11, BAP1, and SF3B1 mutations, and the same chromosome 3 and 8q status as the corresponding patient samples. Six PDX models were challenged with two compounds for 4 weeks. We show that, for 31% of patients with high or intermediate risk of metastasis, the timing to obtain efficacy results on PDX models derived from their primary tumors was compatible with the selection of the therapy to treat the patient after relapse. PDXs could thus be a valid tool (“avatar”) to select the best personalized therapy for one third of patients that are most at risk of relapse. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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15 pages, 7800 KiB  

Open AccessArticle

ATF4 Transcriptionally Activates SHH to Promote Proliferation, Invasion, and Migration of Gastric Cancer Cells

by Yang Wang, Muhammad Ali, Qi Zhang, Qiannan Sun, Jun Ren, Wei Wang, Dong Tang and Daorong Wang

Cancers 2023, 15(5), 1429; https://doi.org/10.3390/cancers15051429 - 23 Feb 2023

Cited by 5 | Viewed by 2364

Abstract

Activating transcription factor 4 (ATF4) is a DNA-binding protein widely generated in mammals, which has two biological characteristics that bind the cAMP response element (CRE). The mechanism of ATF4 as a transcription factor in gastric cancer affecting the Hedgehog pathway remains unclear. Here, [...] Read more.

Activating transcription factor 4 (ATF4) is a DNA-binding protein widely generated in mammals, which has two biological characteristics that bind the cAMP response element (CRE). The mechanism of ATF4 as a transcription factor in gastric cancer affecting the Hedgehog pathway remains unclear. Here, we observed that ATF4 was markedly upregulated in gastric cancer (GC) using immunohistochemistry and Western blotting assays in 80 paraffin-embedded GC samples and 4 fresh samples and para-cancerous tissues. ATF4 knockdown using lentiviral vectors strongly inhibited the proliferation and invasion of GC cells. ATF4 upregulation using lentiviral vectors promoted the proliferation and invasion of GC cells. We predicted that the transcription factor ATF4 is bound to the SHH promoter via the JASPA database. Transcription factor ATF4 is bound to the promoter region of SHH to activate the Sonic Hedgehog pathway. Mechanistically, rescue assays showed that ATF4 regulated gastric cancer cells’ proliferation and invasive ability through SHH. Similarly, ATF4 enhanced the tumor formation of GC cells in a xenograft model. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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15 pages, 3165 KiB  

Open AccessArticle

Expression Profiles of Cuproptosis-Related Genes Determine Distinct Subtypes of Pancreatic Ductal Adenocarcinoma

by Yusheng Chen, Xuan Zou, Mingjian Ma, Yu Liu, Ruijie Wang, Zhengjie Dai, Yesiboli Tashiheng, Yu Yan, Xianjun Yu, Xu Wang, Chen Liu, Xuan Lin and He Cheng

Curr. Oncol. 2023, 30(2), 1648-1662; https://doi.org/10.3390/curroncol30020126 - 29 Jan 2023

Cited by 2 | Viewed by 2676

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent subtype of pancreatic cancer and one of the most malignant tumors worldwide. Due to the heterogeneity of its genomics and proteomics, the prognosis of PDAC remains disappointing despite advances in surgery and medicines. Recently, [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent subtype of pancreatic cancer and one of the most malignant tumors worldwide. Due to the heterogeneity of its genomics and proteomics, the prognosis of PDAC remains disappointing despite advances in surgery and medicines. Recently, a novel form of programmed cell death, cuproptosis, was proposed, although its role in PDAC has not been investigated. This study aimed to quantify the expression of cuproptosis-related genes and characterize the novel subtypes of PDAC. Methods: To evaluate the pattern of cuproptosis in PDAC, the gene expression data and clinical information of 372 samples were collected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A consensus cluster analysis was performed using the transcriptional levels, genetic alterations, and individual prognostic values of seven pre-selected cuproptosis-related genes (DLAT, LIPT1, FDX1, DLD, PDHB, PDHA1, and LIAS) to identify the novel subtypes associated with cuproptosis in PDAC. A univariate Cox regression analysis was used to determine the significant prognostic indicators and cuproptosis scores among the differentially expressed genes (DEGs) between the dividing subclusters, followed by a principal component analysis. The prognostic values, immune profiles, treatment sensitivities, and cuproptosis scores were evaluated between the different subgroups. Results: Seven cuproptosis-related genes showed aberrant expression levels and genetic alterations in the PDAC tumor microenvironment. Among them, LIPT1, LIAS, DLAT, PDHA1, and DLD were significantly correlated with overall survival. Based on the expression profiles of the seven cuproptosis-related genes, three cuproptosis clusters (Clusters A, B, and C) were identified, which were represented by different clinicopathologic features, gene expression levels, and biological processes. A total of 686 DEGs were identified among the three cuproptosis clusters, of which 35 prognosis-related DEGs were selected to further classify the PDAC samples into two subgroups with different survival rates, clinicopathologic features, immune infiltration levels, and drug sensitivities. Higher cuproptosis scores were associated with a significantly poorer prognosis. Conclusion: The cuproptosis subtypes, scores, and relevant genes represent valuable information for assessing the heterogeneity, treatment, and prognosis of PDAC. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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19 pages, 891 KiB  

Open AccessReview

Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy

by Zhujiang Dai, Jihong Fu, Xiang Peng, Dong Tang and Jinglue Song

Cancers 2022, 14(19), 4796; https://doi.org/10.3390/cancers14194796 - 30 Sep 2022

Cited by 4 | Viewed by 2669

Abstract

In recent years, cancer immunotherapy has become a breakthrough method to solve solid tumors. It uses immune checkpoint inhibitors to interfere with tumor immune escape to coordinate anti-tumor therapy. However, immunotherapy has an individualized response rate. Moreover, immune-related adverse events and drug resistance [...] Read more.

In recent years, cancer immunotherapy has become a breakthrough method to solve solid tumors. It uses immune checkpoint inhibitors to interfere with tumor immune escape to coordinate anti-tumor therapy. However, immunotherapy has an individualized response rate. Moreover, immune-related adverse events and drug resistance are still urgent issues that need to be resolved, which may be attributed to the immune imbalance caused by immune checkpoint inhibitors. Microbiome research has fully revealed the metabolic-immune interaction relationship between the microbiome and the host. Surprisingly, sequencing technology further proved that intestinal microbiota could effectively intervene in tumor immunotherapy and reduce the incidence of adverse events. Therefore, cancer immunotherapy under the intervention of intestinal microbiota has innovatively broadened the anti-tumor landscape and is expected to become an active strategy to enhance individualized responses. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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