Topic Editors

Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
The Arkadi M. Rywlin Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA

Molecular and Cellular Mechanisms of Cancers: Colorectal Cancer

Abstract submission deadline
closed (28 December 2022)
Manuscript submission deadline
closed (28 February 2023)
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27395

Topic Information

Dear Colleagues,

Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States. It has always been recognized as a heterogeneous disease, where the clinical course is unique to every patient in terms of prognosis and treatment response. With the rapid advancement in the medical field and the wide use of next-generation sequencing techniques to understand CRC, researchers and physicians are moving away from a “one size fits all” strategy in treating the disease to identifying novel biomarkers that can be targeted to specifically treat every patient. Nevertheless, treatment of most CRC patients requires a multimodality approach that includes surgical intervention, radiation therapy, and chemotherapy. It is thus crucial to decipher the molecular and cellular mechanisms underlying the initiation and progression of this intractable cancer and accordingly identify the unique biomarkers associated with it to aid in cancer diagnosis and improve prognosis. This approach in the management of CRC—by applying basic and translational research with bed-side clinical research—is the hub for “personalized medicine” in the 21st century, and it is an area of great interest to all physicians and researchers working in the field, in particular molecular pathologists and hematology-oncologists. This issue focuses on research and experiences related to CRC. This may include deciphering the molecular and cellular mechanisms underlying the initiation, promotion, and progression of CRC in addition to the identification of novel cancer biomarkers and therapeutic targets, with focus on the prospects for improving personalized cancer care using new technologies to enhance cancer patient diagnoses, management, and outcomes. In this Special Issue, we invite researchers in molecular pathology, hematology–oncology, hematopathology, stem cells, and other fields of cancer research to submit high-quality empirical papers or reviews related to the issues in this research area.

Dr. Wassim Abou-Kheir
Dr. Hisham Bahmad
Topic Editors

Keywords

  • colorectal cancer
  • biomarkers
  • therapeutic target
  • personalized medicine
  • targeted therapy
  • genetic aberrations
  • molecular signatures
  • next generation sequencing

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomolecules
biomolecules
5.5 8.3 2011 16.9 Days CHF 2700
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700
Journal of Molecular Pathology
jmp
- - 2020 24.9 Days CHF 1000
Organoids
organoids
- - 2022 15.0 days * CHF 1000

* Median value for all MDPI journals in the second half of 2023.


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Published Papers (12 papers)

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22 pages, 13691 KiB  
Article
Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling
by Raju Lama Tamang, Balawant Kumar, Sagar M. Patel, Ishwor Thapa, Alshomrani Ahmad, Vikas Kumar, Rizwan Ahmad, Donald F. Becker, Dundy (Kiran) Bastola, Punita Dhawan and Amar B. Singh
Cells 2023, 12(14), 1883; https://doi.org/10.3390/cells12141883 - 18 Jul 2023
Cited by 1 | Viewed by 1535
Abstract
Background: Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon [...] Read more.
Background: Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. Methods: A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. Results: PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. Conclusions: PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer. Full article
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14 pages, 3484 KiB  
Article
Loss of Tumor Suppressor C9orf9 Promotes Metastasis in Colorectal Cancer
by Erfei Chen, Fangfang Yang, Qiqi Li, Tong Li, Danni Yao, Lichao Cao and Jin Yang
Biomolecules 2023, 13(2), 312; https://doi.org/10.3390/biom13020312 - 07 Feb 2023
Cited by 2 | Viewed by 1348
Abstract
The whole genome sequencing of tumor samples identifies thousands of somatic mutations. However, the function of these genes or mutations in regulating cancer progression remains unclear. We previously performed exome sequencing in patients with colorectal cancer, and identified one splicing mutation in C9orf9 [...] Read more.
The whole genome sequencing of tumor samples identifies thousands of somatic mutations. However, the function of these genes or mutations in regulating cancer progression remains unclear. We previously performed exome sequencing in patients with colorectal cancer, and identified one splicing mutation in C9orf9. The subsequent target sequencing of C9orf9 gene based on a validation cohort of 50 samples also found two function mutations, indicating that the loss of wild-type C9orf9 may participate in the tumorigenesis of colorectal cancer. In this research, we aimed to further confirm the function of C9orf9 in the CRC phenotype. Our Q-PCR analysis of the tumor and matched normal samples found that C9orf9 was downregulated in the CRC samples. Function assays revealed that C9orf9 exerts its tumor suppressor role mainly on cancer cell migration and invasion, and its loss was essential for certain tumor-microenvironment signals to induce EMT and metastasis in vivo. RNA-sequencing showed that stable-expressing C9orf9 can inhibit the expression of several metastasis-related genes and pathways, including vascular endothelial growth factor A (VEGFA), one of the essential endothelial cell mitogens which plays a critical role in normal physiological and tumor angiogenesis. Overall, our results showed that the loss of C9orf9 contributes to the malignant phenotype of CRC. C9orf9 may serve as a novel metastasis repressor for CRC. Full article
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20 pages, 9976 KiB  
Article
Prognostic Biomarker SPOCD1 and Its Correlation with Immune Infiltrates in Colorectal Cancer
by Lin Gan, Changjiang Yang, Long Zhao, Shan Wang, Zhidong Gao and Yingjiang Ye
Biomolecules 2023, 13(2), 209; https://doi.org/10.3390/biom13020209 - 20 Jan 2023
Cited by 1 | Viewed by 1562
Abstract
The biological role of the spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) has been investigated in human malignancies, but its function in colorectal cancer (CRC) is unclear. This study investigated the association between SPOCD1 expression and clinicopathological features of CRC cases, [...] Read more.
The biological role of the spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) has been investigated in human malignancies, but its function in colorectal cancer (CRC) is unclear. This study investigated the association between SPOCD1 expression and clinicopathological features of CRC cases, as well as its prognostic value and biological function based on large-scale databases and clinical samples. The results showed that the expression level of SPOCD1 was elevated in CRC, which was generally associated with shortened survival time and poor clinical indexes, including advanced T, N, and pathologic stages. Multivariate Cox regression analysis showed that elevated SPOCD1 expression was an independent factor for poor prognosis in CRC patients. Functional enrichment analysis of SPOCD1 and its co-expressed genes revealed that SPOCD1 could act as an oncogene by regulating gene expression in essential functions and pathways of tumorigenesis, such as extracellular matrix organization, chemokine signaling pathways, and calcium signaling pathways. In addition, immune cell infiltration results showed that SPOCD1 expression was associated with various immune cells, especially macrophages. Furthermore, our findings suggested a possible function for SPOCD1 in the polarization of macrophages from M1 to M2 in CRC. In conclusion, SPOCD1 is a promising diagnostic and prognostic marker for CRC, opening new avenues for research and treatment. Full article
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15 pages, 2356 KiB  
Review
Effects of Long Non-Coding RNAs Induced by the Gut Microbiome on Regulating the Development of Colorectal Cancer
by Shiying Fan, Juan Xing, Zhengting Jiang, Zhilin Zhang, Huan Zhang, Daorong Wang and Dong Tang
Cancers 2022, 14(23), 5813; https://doi.org/10.3390/cancers14235813 - 25 Nov 2022
Cited by 7 | Viewed by 1868
Abstract
Although an imbalanced gut microbiome is closely associated with colorectal cancer (CRC), how the gut microbiome affects CRC is not known. Long non-coding RNAs (lncRNAs) can affect important cellular functions such as cell division, proliferation, and apoptosis. The abnormal expression of lncRNAs can [...] Read more.
Although an imbalanced gut microbiome is closely associated with colorectal cancer (CRC), how the gut microbiome affects CRC is not known. Long non-coding RNAs (lncRNAs) can affect important cellular functions such as cell division, proliferation, and apoptosis. The abnormal expression of lncRNAs can promote CRC cell growth, proliferation, and metastasis, mediating the effects of the gut microbiome on CRC. Generally, the gut microbiome regulates the lncRNAs expression, which subsequently impacts the host transcriptome to change the expression of downstream target molecules, ultimately resulting in the development and progression of CRC. We focused on the important role of the microbiome in CRC and their effects on CRC-related lncRNAs. We also reviewed the impact of the two main pathogenic bacteria, Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, and metabolites of the gut microbiome, butyrate, and lipopolysaccharide, on lncRNAs. Finally, available therapies that target the gut microbiome and lncRNAs to prevent and treat CRC were proposed. Full article
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23 pages, 1144 KiB  
Review
Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis
by Candida Fasano, Valentina Grossi, Giovanna Forte and Cristiano Simone
Cells 2022, 11(23), 3739; https://doi.org/10.3390/cells11233739 - 23 Nov 2022
Cited by 3 | Viewed by 1945
Abstract
Colorectal tumorigenesis is driven by alterations in genes and proteins responsible for cancer initiation, progression, and invasion. This multistage process is based on a dense network of protein–protein interactions (PPIs) that become dysregulated as a result of changes in various cell signaling effectors. [...] Read more.
Colorectal tumorigenesis is driven by alterations in genes and proteins responsible for cancer initiation, progression, and invasion. This multistage process is based on a dense network of protein–protein interactions (PPIs) that become dysregulated as a result of changes in various cell signaling effectors. PPIs in signaling and regulatory networks are known to be mediated by short linear motifs (SLiMs), which are conserved contiguous regions of 3–10 amino acids within interacting protein domains. SLiMs are the minimum sequences required for modulating cellular PPI networks. Thus, several in silico approaches have been developed to predict and analyze SLiM-mediated PPIs. In this review, we focus on emerging evidence supporting a crucial role for SLiMs in driver pathways that are disrupted in colorectal cancer (CRC) tumorigenesis and related PPI network alterations. As a result, SLiMs, along with short peptides, are attracting the interest of researchers to devise small molecules amenable to be used as novel anti-CRC targeted therapies. Overall, the characterization of SLiMs mediating crucial PPIs in CRC may foster the development of more specific combined pharmacological approaches. Full article
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23 pages, 2249 KiB  
Review
The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration
by Zihong Wu, Qiong Ma, Ying Guo and Fengming You
Cancers 2022, 14(21), 5350; https://doi.org/10.3390/cancers14215350 - 30 Oct 2022
Cited by 4 | Viewed by 2749
Abstract
Colorectal cancer (CRC) is a common cancer worldwide with poor prognosis. The presence of Fusobacterium nucleatum (Fn) in the intestinal mucosa is associated with the progression of CRC. In this review, we explore the mechanisms by which Fn contributes to proliferation and migration [...] Read more.
Colorectal cancer (CRC) is a common cancer worldwide with poor prognosis. The presence of Fusobacterium nucleatum (Fn) in the intestinal mucosa is associated with the progression of CRC. In this review, we explore the mechanisms by which Fn contributes to proliferation and migration of CRC cells from the following four aspects: induction of the epithelial–mesenchymal transition (EMT), regulation of the tumor microenvironment (TME), expression of oncogenic noncoding RNAs, and DNA damage. This review outlines the scientific basis for the use of Fn as a biomarker and therapeutic target in CRC. Full article
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17 pages, 1228 KiB  
Review
Zinc Finger Proteins: Functions and Mechanisms in Colon Cancer
by Shujie Liu, Xiaonan Sima, Xingzhu Liu and Hongping Chen
Cancers 2022, 14(21), 5242; https://doi.org/10.3390/cancers14215242 - 26 Oct 2022
Cited by 7 | Viewed by 3023
Abstract
According to the global cancer burden data for 2020 issued by the World Health Organization (WHO), colorectal cancer has risen to be the third-most frequent cancer globally after breast and lung cancer. Despite advances in surgical treatment and chemoradiotherapy for colon cancer, individuals [...] Read more.
According to the global cancer burden data for 2020 issued by the World Health Organization (WHO), colorectal cancer has risen to be the third-most frequent cancer globally after breast and lung cancer. Despite advances in surgical treatment and chemoradiotherapy for colon cancer, individuals with extensive liver metastases still have depressing prognoses. Numerous studies suggest ZFPs are crucial to the development of colon cancer. The ZFP family is encoded by more than 2% of the human genome sequence and is the largest transcriptional family, all with finger-like structural domains that could combine with Zn2+. In this review, we summarize the functions, molecular mechanisms and recent advances of ZFPs in colon cancer. We also discuss how these proteins control the development and progression of colon cancer by regulating cell proliferation, EMT, invasion and metastasis, inflammation, apoptosis, the cell cycle, drug resistance, cancer stem cells and DNA methylation. Additionally, several investigations have demonstrated that Myeloid zinc finger 1 (MZF1) has dual functions in colon cancer, which may both promote cancer proliferation and inhibit cancer progression through apoptosis. Generally, a comprehensive understanding of the action mechanisms of ZFPs in colon cancer will not only shed light on the discovery of new diagnostic and prognosis indicators but will also facilitate the design of novel targeted therapies. Full article
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18 pages, 4132 KiB  
Article
CREPT Disarms the Inhibitory Activity of HDAC1 on Oncogene Expression to Promote Tumorigenesis
by Yajun Cao, Bobin Ning, Ye Tian, Tingwei Lan, Yunxiang Chu, Fangli Ren, Yinyin Wang, Qingyu Meng, Jun Li, Baoqing Jia and Zhijie Chang
Cancers 2022, 14(19), 4797; https://doi.org/10.3390/cancers14194797 - 30 Sep 2022
Cited by 2 | Viewed by 1630
Abstract
Histone deacetylases 1 (HDAC1), an enzyme that functions to remove acetyl molecules from ε-NH3 groups of lysine in histones, eliminates the histone acetylation at the promoter regions of tumor suppressor genes to block their expression during tumorigenesis. However, it remains unclear why HDAC1 [...] Read more.
Histone deacetylases 1 (HDAC1), an enzyme that functions to remove acetyl molecules from ε-NH3 groups of lysine in histones, eliminates the histone acetylation at the promoter regions of tumor suppressor genes to block their expression during tumorigenesis. However, it remains unclear why HDAC1 fails to impair oncogene expression. Here we report that HDAC1 is unable to occupy at the promoters of oncogenes but maintains its occupancy with the tumor suppressors due to its interaction with CREPT (cell cycle-related and expression-elevated protein in tumor, also named RPRD1B), an oncoprotein highly expressed in tumors. We observed that CREPT competed with HDAC1 for binding to oncogene (such as CCND1, CLDN1, VEGFA, PPARD and BMP4) promoters but not the tumor suppressor gene (such as p21 and p27) promoters by a chromatin immunoprecipitation (ChIP) qPCR experiment. Using immunoprecipitation experiments, we deciphered that CREPT specifically occupied at the oncogene promoter via TCF4, a transcription factor activated by Wnt signaling. In addition, we performed a real-time quantitative PCR (qRT-PCR) analysis on cells that stably over-expressed CREPT and/or HDAC1, and we propose that HDAC1 inhibits CREPT to activate oncogene expression under Wnt signaling activation. Our findings revealed that HDAC1 functions differentially on tumor suppressors and oncogenes due to its interaction with the oncoprotein CREPT. Full article
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14 pages, 74690 KiB  
Article
Nuclear Beclin 1 Destabilizes Retinoblastoma Protein to Promote Cell Cycle Progression and Colorectal Cancer Growth
by Yang Pan, Zhiqiang Zhao, Juan Li, Jinsong Li, Yue Luo, Weiyuxin Li, Wanbang You, Yujun Zhang, Zhonghan Li, Jian Yang, Zhi-Xiong Jim Xiao and Yang Wang
Cancers 2022, 14(19), 4735; https://doi.org/10.3390/cancers14194735 - 28 Sep 2022
Cited by 5 | Viewed by 2151
Abstract
Autophagy is elevated in colorectal cancer (CRC) and is generally associated with poor prognosis. However, the role of autophagy core-protein Beclin 1 remains controversial in CRC development. Here, we show that the expression of nuclear Beclin 1 protein is upregulated in CRC with [...] Read more.
Autophagy is elevated in colorectal cancer (CRC) and is generally associated with poor prognosis. However, the role of autophagy core-protein Beclin 1 remains controversial in CRC development. Here, we show that the expression of nuclear Beclin 1 protein is upregulated in CRC with a negative correlation to retinoblastoma (RB) protein expression. Silencing of BECN1 upregulates RB resulting in cell cycle G1 arrest and growth inhibition of CRC cells independent of p53. Furthermore, ablation of BECN1 inhibits xenograft tumor growth through elevated RB expression and reduced autophagy, while simultaneous silencing of RB1 restores tumor growth but has little effect on autophagy. Mechanistically, knockdown of BECN1 promotes the complex formation of MDM2 and MDMX, resulting in MDM2-dependent MDMX instability and RB stabilization. Our results demonstrate that nuclear Beclin 1 can promote cell cycle progression through modulation of the MDM2/X-RB pathway and suggest that Beclin 1 promotes CRC development by facilitating both cell cycle progression and autophagy. Full article
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16 pages, 1749 KiB  
Article
Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis
by Esther Schamschula, Miriam Kinzel, Annekatrin Wernstedt, Klaus Oberhuber, Hendrik Gottschling, Simon Schnaiter, Nicolaus Friedrichs, Sabine Merkelbach-Bruse, Johannes Zschocke, Richard Gallon and Katharina Wimmer
Biomolecules 2022, 12(10), 1350; https://doi.org/10.3390/biom12101350 - 22 Sep 2022
Cited by 10 | Viewed by 2534
Abstract
Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of [...] Read more.
Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd. Full article
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23 pages, 3866 KiB  
Article
Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells
by Mark F. Santos, Germana Rappa, Simona Fontana, Jana Karbanová, Feryal Aalam, Derek Tai, Zhiyin Li, Marzia Pucci, Riccardo Alessandro, Chikao Morimoto, Denis Corbeil and Aurelio Lorico
Cells 2022, 11(16), 2474; https://doi.org/10.3390/cells11162474 - 10 Aug 2022
Cited by 7 | Viewed by 3136
Abstract
Intercellular communication between cancer cells themselves or with healthy cells in the tumor microenvironment and/or pre-metastatic sites plays an important role in cancer progression and metastasis. In addition to ligand–receptor signaling complexes, extracellular vesicles (EVs) are emerging as novel mediators of intercellular communication [...] Read more.
Intercellular communication between cancer cells themselves or with healthy cells in the tumor microenvironment and/or pre-metastatic sites plays an important role in cancer progression and metastasis. In addition to ligand–receptor signaling complexes, extracellular vesicles (EVs) are emerging as novel mediators of intercellular communication both in tissue homeostasis and in diseases such as cancer. EV-mediated transfer of molecular activities impacting morphological features and cell motility from highly metastatic SW620 cells to non-metastatic SW480 cells is a good in vitro example to illustrate the increased malignancy of colorectal cancer leading to its transformation and aggressive behavior. In an attempt to intercept the intercellular communication promoted by EVs, we recently developed a monovalent Fab fragment antibody directed against human CD9 tetraspanin and showed its effectiveness in blocking the internalization of melanoma cell-derived EVs and the nuclear transfer of their cargo proteins into recipient cells. Here, we employed the SW480/SW620 model to investigate the anti-cancer potential of the anti-CD9 Fab antibody. We first demonstrated that most EVs derived from SW620 cells contain CD9, making them potential targets. We then found that the anti-CD9 Fab antibody, but not the corresponding divalent antibody, prevented internalization of EVs from SW620 cells into SW480 cells, thereby inhibiting their phenotypic transformation, i.e., the change from a mesenchymal-like morphology to a rounded amoeboid-like shape with membrane blebbing, and thus preventing increased cell migration. Intercepting EV-mediated intercellular communication in the tumor niche with an anti-CD9 Fab antibody, combined with direct targeting of cancer cells, could lead to the development of new anti-cancer therapeutic strategies. Full article
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17 pages, 3568 KiB  
Article
Single-Cell FISH Analysis Reveals Distinct Shifts in PKM Isoform Populations during Drug Resistance Acquisition
by Seong Ho Kim, Ji Hun Wi, HyeRan Gwak, Eun Gyeong Yang and So Yeon Kim
Biomolecules 2022, 12(8), 1082; https://doi.org/10.3390/biom12081082 - 06 Aug 2022
Cited by 1 | Viewed by 1841
Abstract
The Warburg effect, i.e., the utilization of glycolysis under aerobic conditions, is recognized as a survival advantage of cancer cells. However, how the glycolytic activity is affected during drug resistance acquisition has not been explored at single-cell resolution. Because the relative ratio of [...] Read more.
The Warburg effect, i.e., the utilization of glycolysis under aerobic conditions, is recognized as a survival advantage of cancer cells. However, how the glycolytic activity is affected during drug resistance acquisition has not been explored at single-cell resolution. Because the relative ratio of the splicing isoform of pyruvate kinase M (PKM), PKM2/PKM1, can be used to estimate glycolytic activity, we utilized a single-molecule fluorescence in situ hybridization (SM-FISH) method to simultaneously quantify the mRNA levels of PKM1 and PKM2. Treatment of HCT116 cells with gefitinib (GE) resulted in two distinct populations of cells. However, as cells developed GE resistance, the GE-sensitive population with reduced PKM2 expression disappeared, and GE-resistant cells (Res) demonstrated enhanced PKM1 expression and a tightly regulated PKM2/PKM1 ratio. Our data suggest that maintaining an appropriate PKM2 level is important for cell survival upon GE treatment, whereas increased PKM1 expression becomes crucial in GE Res. This approach demonstrates the importance of single-cell-based analysis for our understanding of cancer cell metabolic responses to drugs, which could aid in the design of treatment strategies for drug-resistant cancers. Full article
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