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Cells
Special Issues
Molecular and Cellular Underpinnings of Cancer Vulnerability
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Molecular and Cellular Underpinnings of Cancer Vulnerability

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 15279

Special Issue Editors

Prof. Dr. Debabrata Mukhopadhyay

E-Mail Website
Guest Editor
Mayo Clinic in Jacksonville, Florida, Jacksonville, FL, USA
Interests: tumor microenvironment; cancer omics; angiogenesis; drug discovery
Prof. Dr. Sooryanarayana Varambally

E-Mail Website
Guest Editor
1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
2. O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
Interests: cancer molecular genetics; cancer biology and therapeutic targeting

Special Issue Information

Dear Colleagues,

It has become apparent that the molecular and cellular components associated with vulnerability to cancer are uniquely dependent on the type of cancer and whether the tumor has metastasized to specific organ sites in the patient. Understanding and targeting unique driver traits in cancer is critical in the treatment and outcome of precision oncology. The accurate selection of cancer targets and their most effective treatments requires rapid access not only to molecular and cellular analysis of the tumor but also a comparative profile of various treatments that have proved effective against specific genomic alterations. This Special Issue will highlight the differential expression of genes and their mutations as well as cellular alterations that constitute diverse cancers and discuss the impact of the vulnerabilities in various geographical regions of the world. Correlation of driver traits with overall survival and/or progression-free survival outcomes will also be included to guide global oncology researchers and clinicians to identify cancer-specific molecular and cellular alterations and response to treatment in diverse parts of the world.

Prof. Dr. Debabrata Mukhopadhyay
Prof. Dr. Sooryanarayana Varambally
Guest Editors

Manuscript Submission Information

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Keywords

  • multi-omics
  • genomics
  • precision oncology
  • racial disparity

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Published Papers (5 papers)

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Research

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17 pages, 3991 KiB  
Article
Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells
by Shaymaa Sadeq, Suwalak Chitcharoen, Surar Al-Hashimi, Somruthai Rattanaburi, John Casement and Andreas Werner
Cells 2024, 13(3), 226; https://doi.org/10.3390/cells13030226 - 25 Jan 2024
Viewed by 2683
Abstract
Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic [...] Read more.
Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic activation of innate immune pathways is associated with various diseases and senescence and can trigger apoptosis. Hereby, the level of cytoplasmic dsRNA is crucial. We have enriched dsRNA from two melanoma cell lines and primary dermal fibroblasts, including a competing probe, and analyzed the dsRNA transcriptome using RNA sequencing. There was a striking difference in read counts between the cell lines and the primary cells, and the effect was confirmed by northern blotting and immunocytochemistry. Both mitochondria (10–20%) and nuclear transcription (80–90%) contributed significantly to the dsRNA transcriptome. The mitochondrial contribution was lower in the cancer cells compared to fibroblasts. The expression of different transposable element families was comparable, suggesting a general up-regulation of transposable element expression rather than stimulation of a specific sub-family. Sequencing of the input control revealed minor differences in dsRNA processing pathways with an upregulation of oligoadenylate synthase and RNP125 that negatively regulates the dsRNA sensors RIG1 and MDA5. Moreover, RT-qPCR, Western blotting, and immunocytochemistry confirmed the relatively minor adaptations to the hugely different dsRNA levels. As a consequence, these transformed cell lines are potentially less tolerant to interventions that increase the formation of endogenous dsRNA. Full article
(This article belongs to the Special Issue Molecular and Cellular Underpinnings of Cancer Vulnerability)
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21 pages, 14357 KiB  
Article
TGFβ and Hippo Signaling Pathways Coordinate to Promote Acinar to Ductal Metaplasia in Human Pancreas
by Michael Nipper, Yi Xu, Jun Liu, Xue Yin, Zhijie Liu, Zhengqing Ye, Jianmin Zhang, Yidong Chen and Pei Wang
Cells 2024, 13(2), 186; https://doi.org/10.3390/cells13020186 - 18 Jan 2024
Cited by 2 | Viewed by 2809
Abstract
Background & Aims: Acinar-to-ductal metaplasia (ADM) serves as a precursor event in the development of pancreatic ductal adenocarcinoma (PDAC) upon constitutive environmental and genetical stress. While the role of ADM in PDAC progression has been established, the molecular mechanisms underlying human ADM remain [...] Read more.
Background & Aims: Acinar-to-ductal metaplasia (ADM) serves as a precursor event in the development of pancreatic ductal adenocarcinoma (PDAC) upon constitutive environmental and genetical stress. While the role of ADM in PDAC progression has been established, the molecular mechanisms underlying human ADM remain elusive. We previously demonstrated the induction of ADM in human acinar cells through the transforming growth factor beta (TGFβ) signaling pathway. We aim to investigate the interaction between TGFβ and Hippo pathways in mediating ADM. Methods: RNA-sequencing was conducted on sorted normal primary human acinar, ductal, and AD (acinar cells that have undergone ADM) cells. ATAC-seq analysis was utilized to reveal the chromatin accessibility in these three cell types. ChIP-Seq of YAP1, SMAD4, and H3K27ac was performed to identify the gene targets of YAP1 and SMAD4. The role of YAP1/TAZ in ADM-driven cell proliferation, as well as in oncogenic KRAS driven proliferation, was assessed using sphere formation assay. Results: AD cells have a unique transcription profile, with upregulated genes in open chromatin states in acinar cells. YAP1 and SMAD4 co-occupy the loci of ADM-related genes, including PROM1, HES1, and MMP7, co-regulating biological functions such as cell adhesion, cell migration, and inflammation. Overexpression of YAP1/TAZ promoted acinar cell proliferation but still required the TGFβ pathway. YAP1/TAZ were also crucial for TGFβ-induced sphere formation and were necessary for KRAS-induced proliferation. Conclusions: Our study reveals the intricate transition between acinar and AD states in human pancreatic tissues. It unveils the complex interaction between the Hippo and TGF-β pathways during ADM, highlighting the pivotal role of YAP1/TAZ and SMAD4 in PDAC initiation. Full article
(This article belongs to the Special Issue Molecular and Cellular Underpinnings of Cancer Vulnerability)
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15 pages, 2592 KiB  
Article
Increased Gene Expression of C1orf74 Is Associated with Poor Prognosis in Cervical Cancer
by Preetiparna Parida, Shirley Lewis, Krishna Sharan, Mehta Vedant Kamal, Naveena A. N. Kumar, Vishwapriya M. Godkhindi, Sooryanarayana Varambally, Vivek M. Rangnekar, Mahadev Rao and Rama Rao Damerla
Cells 2023, 12(21), 2530; https://doi.org/10.3390/cells12212530 - 27 Oct 2023
Cited by 3 | Viewed by 2464
Abstract
C1orf74, also known as URCL4, has been reported to have higher expression and be associated with poor prognosis in lung adenocarcinoma patients, and its role in regulation of the EGFR/AKT/mTORC1 pathway has been recently elucidated. In the current study, we used publicly [...] Read more.
C1orf74, also known as URCL4, has been reported to have higher expression and be associated with poor prognosis in lung adenocarcinoma patients, and its role in regulation of the EGFR/AKT/mTORC1 pathway has been recently elucidated. In the current study, we used publicly available data and experimental validation of C1orf74 gene expression and its association with prognosis in cervical cancer patients. qRT-PCR was performed using RNA from cervical cancer cell lines and twenty-five cervical cancer patients. Data from TNMplot revealed that mRNA expression of the C1orf74 gene in primary tumor tissues, as well as metastatic tissues from cervical cancer patients, was significantly higher compared to normal cervical tissues. HPV-positive tumors had higher expression of this gene compared to HPV-negative tumors. qPCR analysis also demonstrated higher expression of C1orf74 in HPV-positive cervical cancer cell lines and most cervical cancer patients. The promoter methylation levels of the C1orf74 gene in cervical cancer tissues were lower compared to normal cervical tissues (p < 0.05). Collectively, our study indicates that higher expression of the C1orf74 gene caused by hypomethylation of its promoter is associated with poor overall survival in cervical cancer patients. Thus, C1orf74 is a novel prognostic marker in cervical cancer. Full article
(This article belongs to the Special Issue Molecular and Cellular Underpinnings of Cancer Vulnerability)
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Review

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25 pages, 8967 KiB  
Review
Prognostic Indicators for Precision Treatment of Non-Small Cell Lung Carcinoma
by Damayanti Das Ghosh, Hannah McDonald, Rajeswari Dutta, Keerthana Krishnan, Jaya Thilakan, Manash K. Paul, Neha Arya, Mahadev Rao and Vivek M. Rangnekar
Cells 2024, 13(21), 1785; https://doi.org/10.3390/cells13211785 - 28 Oct 2024
Cited by 2 | Viewed by 1736
Abstract
Non-small cell lung cancer (NSCLC) has established predictive biomarkers that enable decisions on treatment regimens for many patients. However, resistance to therapy is widespread. It is therefore essential to have a panel of molecular biomarkers that may help overcome therapy resistance and prevent [...] Read more.
Non-small cell lung cancer (NSCLC) has established predictive biomarkers that enable decisions on treatment regimens for many patients. However, resistance to therapy is widespread. It is therefore essential to have a panel of molecular biomarkers that may help overcome therapy resistance and prevent adverse effects of treatment. We performed in silico analysis of NSCLC prognostic indicators, separately for adenocarcinomas and squamous carcinomas, by using The Cancer Genome Atlas (TCGA) and non-TCGA data sources in cBioPortal as well as UALCAN. This review describes lung cancer biology, elaborating on the key genetic alterations and specific genes responsible for resistance to conventional treatments. Importantly, we examined the mechanisms associated with resistance to immune checkpoint inhibitors. Our analysis indicated that a robust prognostic biomarker was lacking for NSCLC, especially for squamous cell carcinomas. In this work, our screening uncovered previously unidentified prognostic gene expression indicators, namely, MYO1E, FAM83 homologs, and DKK1 for adenocarcinoma, and FGA and TRIB1 for squamous cell carcinoma. It was further observed that overexpression of these genes was associated with poor prognosis. Additionally, FAM83 homolog and TRIB1 unexpectedly harbored copy number amplifications. In conclusion, this study elucidated novel prognostic indicators for NSCLC that may serve as targets to overcome therapy resistance toward improved patient outcomes. Full article
(This article belongs to the Special Issue Molecular and Cellular Underpinnings of Cancer Vulnerability)
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39 pages, 21495 KiB  
Review
KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways
by Koushik Mondal, Mahesh Kumar Posa, Revathi P. Shenoy and Susanta Roychoudhury
Cells 2024, 13(14), 1221; https://doi.org/10.3390/cells13141221 - 19 Jul 2024
Cited by 6 | Viewed by 4780
Abstract
The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of [...] Read more.
The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of KRAS and any correlations between KRAS and other driver mutations. To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, and Uniport studies. We aimed to unravel the complexity of KRAS and its relationships with other driver mutations. We noticed that G12D and G12V are the prevalent mutated variants of KRAS and coexist with the TP53 mutation in PAAD and CRAD, while G12C and G12V coexist with LUAD. We also noticed similar observations in the case of PIK3CA and APC mutations in CRAD. At the transcript level, a positive correlation exists between KRAS and PIK3CA and between APC and KRAS in CRAD. The existence of the co-mutation of KRAS and other driver mutations could influence the signaling pathway in the neoplastic transformation. Moreover, it has immense prognostic and predictive implications, which could help in better therapeutic management to treat cancer. Full article
(This article belongs to the Special Issue Molecular and Cellular Underpinnings of Cancer Vulnerability)
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