Malignant Phenotype Of Cancer Cells Research Articles

The Effect of Co-Delivery of Oxygen and Anticancer Drugs on the Viability of Healthy and Cancer Cells under Normoxic and Hypoxic Conditions.

Hypoxia, cancer, tissue damage, and acidic pH conditions are interrelated, as chronic hypoxic conditions enhance the malignant phenotype of cancer cells, causing more aggressive tissue destruction, and hypoxic cells rely on anaerobic glycolysis, leading to the accumulation of lactic acid. Therefore, the administration of oxygen is necessary to support the functions of healthy cells until the formation of new blood vessels and to increase the oxygen supply to cancerous tissues to improve the efficacy of antitumor drugs on tumor cells. In addition to O2 supply, pH-dependent delivery of anticancer drugs is desired to target cancer cells and reduce drug side effects on healthy cells. However, the simultaneous delivery of O2 and pH-dependent anticancer drugs via nanomaterials and their effects on the viability of normal and cancer cells under hypoxic conditions have not been studied in sufficient numbers. This study describes the synthesis of a pH-responsive nanomaterial containing oxygen and anticancer drugs that exhibits sustained O2 release over a 14 d period under hypoxic conditions and pH-dependent sustained release of anticancer drugs over 30 d. The simultaneous administration of O2 and anticancer drugs results in higher cell survival of normal cells than that of cancer cells under hypoxic and normoxic conditions.

ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression

Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remain poorly understood. Here, we use the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we design a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulates MYC expression and inhibits the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20–YTHDF3–MYC signaling axis in pancreatic cancer.

Abstract 4779: The effects of glutamine deprivation on ovarian cancer initiation and progression

Abstract High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. Most patients with HGSC are diagnosed at advanced stage diseases. Despite the high response rate to platinum/taxane-based chemotherapy, most of these patients will develop recurrent chemoresistant disease. Recent studies showed the cancer associated fibroblasts (CAFs) in the tumor microenvironment (TME) play an important role in modulating the malignant phenotypes of HGSC. CAFs are primarily responsible for producing factors such as cytokines and growth factors to modify the TME niche to promote the malignant phenotypes of cancer cells. Recently, we have identified a previously unrecognized mechanism in which metabolism of reactive CAFs is reprogrammed through an upregulated glutamine anabolic pathway in HGSC. This dysfunctional CAF metabolism confers atypical metabolic flexibility and adaptive mechanisms in CAFs, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in the TME. Our preliminary data show that tumors developed from syngeneic fallopian epithelial cell-derived cancer cells injected IP into C57BL/6 mice, which started to be fed with normal diet two weeks before tumor cells injection had significantly higher tumor burden than those fed with the glutamine-deprived diet. Moreover, tumor-bearing mice treated with glutaminase inhibitor for 3 weeks demonstrated significantly lower tumor burden than those treated with the control vehicle. These findings suggest that the interplay between CAFs and HGSC cells enriches glutamine in the ovarian TME; and glutamine depletion can not only suppress ovarian tumor growth but also prevent the development of advanced progressive diseases. In addition to the direct promoting effect of glutamine on the glutamine addicted HGSC cells, increased CAF-derived glutamine can also affect the activity of other stromal cell types such as immune cells in the TME, which subsequently modulate HGSC cell growth. Imaging mass cytometry (IMC) and Mass Spectrometry Imaging (MSI) were performed on serial tissue sections of tissue microarrays generated from the abovementioned murine samples. Mice fed with a glutamine-deprived diet or treated with the glutaminase inhibitor not only have a significantly lower tumor burden but also induced dramatic changes in the cellular and molecular composition within the TME. In particular, mice fed with a glutamine-deprived diet had greater B-cell-related immune response, reduced stemness, and EMT of ovarian cancer cells, and more activated CAFs, which may result in increased stiffness of the ECM and subsequently enhance the malignant phenotype of HGSC cells. Further studies to delineate the molecular mechanisms by which spatial cellular and metabolic profiles modulate HGSC pathogenesis and progression are warranted. Citation Format: Sammy Ferri-Borgogno, Kathryn Lu, Basant T. Gamal, Chi Lam Au Yeung, Erin Seeley, Javier A. Gomez, Akshay Basi, Jared K. Burks, Olamide Animasahun, Deepak Nagrath, Samuel C. Mok. The effects of glutamine deprivation on ovarian cancer initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4779.

M2 macrophage-derived extracellular vesicles augment immune evasion and development of colorectal cancer via a circRNA_CCDC66/microRNA-342-3p/metadherin axis.

The M2 macrophages are major components in the tumor microenvironment and are closely linked to immune suppression and tumor metastasis. This work focuses on how M2 macrophage-derived extracellular vesicles (EVs) affect colorectal cancer (CRC) progression. THP-1 monocytes were induced to differentiate to M0 or M2 macrophages, and the macrophage-derived EVs (M0-EVs and M2-EVs, respectively) were collected and identified. The M2-EVs stimulation augmented proliferation, mobility, and the in vivo tumorigenic activity of CRC cells. Circular RNA_CCDC66 (circ_CCDC66) was highly enriched in M2-EVs and could be delivered into CRC cells. The RNA pull-down and luciferase assays showed that circ_CCDC66 could competitively bind to microRNA (miR)-342-3p, therefore restoring the expression of metadherin (MTDH) mRNA, a target transcript of miR-342-3p. Suppression of circ_CCDC66 in the M2-EVs or specific knockdown of MTDH in CRC significantly blocked the growth and mobility of CRC cells. However, miR-342-3p inhibition restored the malignant phenotype of cancer cells. Moreover, the MTDH knockdown was found to increase the cytotoxicity of CD8+ T and reduce the protein level of the immune checkpoint PDL1 in CRC cells. In summary, this study reveals that the M2-EVs augment immune evasion and development of CRC by delivering circ_CCDC66 and restoring the MTDH level.

The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside

Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.

CCAT 1- A Pivotal Oncogenic Long Non-Coding RNA in Colorectal Cancer.

Colorectal cancer (CRC) is ranked as the third most common cancer and second deadliest cancer in both men and women in the world. Currently, the cure rate and 5-year survival rate of CRC patients remain relatively low. Therefore, discovering a novel molecular biomarker that can be used to improve CRC screening, diagnosis, prognosis, and treatment would be beneficial. Long non-coding RNA colon cancer-associated transcript 1 (CCAT 1) has been found overexpressed in CRC and is associated with CRC tumorigenesis and treatment outcome. CCAT 1 has a high degree of specificity and sensitivity, it is readily detected in CRC tissues and is significantly overexpressed in both premalignant and malignant CRC tissues. Besides, CCAT 1 is associated with clinical manifestation and advanced features of CRC, such as lymph node metastasis, high tumor node metastasis stage, differentiation, invasion, and distant metastasis. In addition, they can upregulate oncogenic c-MYC and negatively modulate microRNAs via different mechanisms of action. Furthermore, dysregulated CCAT 1 also enhances the chemoresistance in CRC cells while downregulation of them reverses the malignant phenotypes of cancer cells. In brief, CCAT 1 serves as a potential screening, diagnostic and prognostic biomarker in CRC, it also serves as a potential therapeutic marker to treat CRC patients.

Roles of IL-7R Induced by Interactions between Cancer Cells and Macrophages in the Progression of Esophageal Squamous Cell Carcinoma.

High infiltration of tumor-associated macrophages (TAMs), which contribute to the progression of several cancer types, is correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). In addition to the previously reported increase in migration and invasion, ESCC cells co-cultured directly with macrophages exhibited enhanced survival and growth. Furthermore, interleukin-related molecules are associated with ESCC; however, the precise mechanism underlying this association is unclear. Therefore, we explored the role of interleukin-related molecules in ESCC progression. A cDNA microarray analysis of monocultured and co-cultured ESCC cells revealed that the interleukin 7 receptor (IL-7R) was upregulated in ESCC cells co-cultured with macrophages. Overexpression of IL-7R promoted the survival and growth of ESCC cells by activating the Akt and Erk1/2 signaling pathways. The IL-7/IL-7R axis also contributed to the promotion of ESCC cell migration via the Akt and Erk1/2 signaling pathways. Furthermore, immunohistochemistry showed that ESCC patients with high IL-7R expression in cancer nests exhibited a trend toward poor prognosis in terms of disease-free survival, and showed significant correlation with increased numbers of infiltrating macrophages and cancer-associated fibroblasts. Therefore, IL-7R, which is upregulated when directly co-cultured with macrophages, may contribute to ESCC progression by promoting the development of various malignant phenotypes in cancer cells.

ARL11 correlates with the immunosuppression and poor prognosis in breast cancer: A comprehensive bioinformatics analysis of ARL family members

ADP-ribosylation factor-like protein (ARL) family members (ARLs) may regulate the malignant phenotypes of cancer cells. However, relevant studies on ARLs in breast cancer (BC) are limited. In this research, the expression profiles, genetic variations, and prognostic values of ARLs in BC have been systematically analyzed for the first time using various databases. We find that ARLs are significantly dysregulated in BC according to the TCGA database, which may result from DNA methylation and copy number alteration. Prognostic analysis suggests that ARL11 is the most significant prognostic indicator for BC, and higher ARL11 predicts worse clinical outcomes for BC patients. Further functional enrichment analysis demonstrates that ARL11 enhances the immunosuppression in BC, and dysregulation of ARL11 is significantly associated with immune infiltration in various types of cancer. Our results demonstrate the potential of ARL11 as an immune therapeutic target for BC.

PRMT5 promotes retinoblastoma development.

Epigenetic mechanism, including DNA methylation and histone modifications, contributes to alterations in the expression patterns of genes regulating malignant phenotype of cancer cells. However, the epigenetic modulation of vascular endothelial growth factor-A (VEGFA) in retinoblastoma (RB) has not been clearly established. We aimed to examine the epigenetic regulation of VEGFA by protein arginine methyltransferase 5 (PRMT5) in RB. Using the GEO database, we identified VEGFA as a pathogenic gene in RB. Silencing of VEGFA in SO-RB50 and Y79 cells inhibited cell proliferation, angiogenesis, and migration, promoted apoptosis, and suppressed tumor growth in mice. Mechanistically, PRMT5 promoted H3K4me3 modification of the VEGFA promoter, thereby activating VEGFA expression. VEGFA could regulate the expression of MMP1, MMP2, and MMP9. Further silencing of VEGFA in RB cells overexpressing PRMT5 constrained the expression of MMP1, MMP2 and MMP9, and suppressed the growth of tumors in mice. In conclusion, this study clarifies that the depletion of PRMT5 reduces H3K4me3-mediated VEGFA transcription and retards the carcinogenesis of RB by suppressing the expression of MMPs.

Hyperglycemia and cancer in human lung carcinoma by means of Raman spectroscopy and imaging

Raman spectroscopy and Raman imaging were used to identify the biochemical and structural features of human cancer lung cells (CCL-185) and the cancer cells supplemented with glucose and deuterated glucose at normal and hyperglycemia conditions. We found that isotope substitution of glucose by deuterated glucose allows to separate de novo lipid synthesis from exogenous uptake of lipids obtained from the diet. We demonstrated that glucose is largely utilized for de novo lipid synthesis. Our results provide a direct evidence that high level of glucose decreases the metabolism via oxidative phosphorylation in mitochondria in cancer cells and shifts the metabolism to glycolysis via Warburg effect. It suggests that hyperglycemia is a factor that may contribute to a more malignant phenotype of cancer cells by inhibition of oxidative phosphorylation and apoptosis.

DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism

The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/NADPH-dependent SDR family, and extensively participates in the regulation of the proliferation, migration, and chemoresistance of cancer cells. However, the underlying mechanism has not been well defined. In the present study, we have demonstrated that DHRS2 inhibits the growth and metastasis of ovarian cancer (OC) cells in vitro and in vivo. Mechanistically, the combination of transcriptome and metabolome reveals an interruption of choline metabolism by DHRS2. DHRS2 post-transcriptionally downregulates choline kinase α (CHKα) to inhibit AKT signaling activation and reduce phosphorylcholine (PC)/glycerophosphorylcholine (GPC) ratio, impeding choline metabolism reprogramming in OC. These actions mainly account for the tumor-suppressive role of DHRS2 in OC. Overall, our findings establish the mechanistic connection among metabolic enzymes, metabolites, and the malignant phenotype of cancer cells. This could result in further development of novel pharmacological tools against OC by the induction of DHRS2 to disrupt the choline metabolic pathway.

WTAP mediates FOXP3 mRNA stability to promote SMARCE1 expression and augment glycolysis in colon adenocarcinoma.

N6-methyladenosine (m6A) is the most abundant mRNA internal modification and has reportedly been linked to aerobic glycolysis, a hallmark event in tumor development. This work focuses on the role of the m6A methyltransferase WT1-associated protein (WTAP) in metabolic reprogramming and development of colon adenocarcinoma (COAD) and the molecules involved. The WTAP expression in COAD tissues and cells was detected. WTAP was knocked down in two COAD cell lines to figure out its role in the glycolytic activity and malignant phenotype of cancer cells. Cancer cells were further injected into nude mice subcutaneously or via tail vein to evaluate tumor growth and metastasis. The downstream molecules involved were explored using bioinformatics tools, and the molecular interactions were confirmed by immunoprecipitation, luciferase assays, and rescue experiments. WTAP was abundantly expressed in COAD samples. Knockdown of WTAP suppressed glucose consumption, lactate production, and glycolysis, which consequently suppressed cancer cell growth and dissemination in vitro and in vivo. WTAP promoted m6A methylation and stabilized forkhead box P3 (FOXP3) mRNA with the participation of the m6A "reader" YTHDF1. FOXP3 could further bind to SMARCE1 promoter for transcriptional activation. Rescue experiments showed that upregulation of FOXP3 or SMARCE1 restored the glycolytic activity in COAD cells and augmented the growth and mobility of cells both in vitro and in vivo. This study demonstrates that WTAP grants glycolytic activity to COAD and promotes tumor malignant development via the m6A modification of FOXP3 mRNA and the upregulation of SMARCE1.

Arctigenin impairs UBC12 enzyme activity and cullin neddylation to attenuate cancer cells.

Neddylation is a type of posttranslational protein modification that has been observed to be overactivated in various cancers. UBC12 is one of two key E2 enzymes in the neddylation pathway. Reports indicate that UBC12 deficiency may suppress lung cancer cells, such that UBC12 could play an important role in tumor progression. However, systematic studies regarding the expression profile of UBC12 in cancers and its relationship to cancer prognosis are lacking. In this study, we comprehensively analyzed UBC12 expression in diverse cancer types and found that UBC12 is markedly overexpressed in most cancers (17/21), a symptom that negatively correlates with the survival rates of cancer patients, including gastric cancer. These results demonstrate the suitability of UBC12 as a potential target for cancer treatment. Currently, no effective inhibitor targeting UBC12 has been discovered. We screened a natural product library and found, for the first time, that arctigenin has been shown to significantly inhibit UBC12 enzyme activity and cullin neddylation. The inhibition of UBC12 enzyme activity was newly found to contribute to the effects of arctigenin on suppressing the malignant phenotypes of cancer cells. Furthermore, we performed proteomics analysis and found that arctigenin intervened with cullin downstream signaling pathways and substrates, such as the tumor suppressor PDCD4. In summary, these results demonstrate the importance of UBC12 as a potential therapeutic target for cancer treatment, and, for the first time, the suitability of arctigenin as a potential compound targeting UBC12 enzyme activity. Thus, these findings provide a new strategy for inhibiting neddylation-overactivated cancers.

Circ_0008287 promotes immune escape of gastric cancer cells through impairing microRNA-548c-3p-dependent inhibition of CLIC1

BackgroundAnalyses in silico suggested the upregulation of a circular RNA (circRNA), circ_0008287, in gastric cancer and possible interactions among microRNA (miR)-548c-3p, circ_0008287, and intracellular chloride channel protein 1 (CLIC1). This study aims to testify whether circ_0008287 can affect the immune escape of gastric cancer cells by regulating miR-548c-3p and CLIC1. MethodsRT-qPCR was performed to determine the expression pattern of circ_0008287 in gastric cancer cells. Gain- and loss-of function assays were then performed to assess the effects of circ_0008287 on malignant phenotypes of cancer cells. Interactions among circ_0008287, miR-548c-3p and CLIC1 were verified by dual luciferase reporter gene, RIP and FISH assays. Effects of CLIC1 on IFN-γ secretion and apoptosis in CD8 + T cells were evaluated by flow cytometry following co-culture of CD8 + T cells with cancer cells overexpressing/silencing CLIC1. A gastric cancer mouse model was further developed for in vivo investigation on effects of circ_0008287 on tumorigenesis and tumor metastasis. Resultscirc_0008287, an upregulated circRNA in gastric cancer cells, augmented the viability as well as invasive and migratory potentials of gastric cancer cells. By competitively binding to miR-548c-3, circ_0008287 increased the expression of CLIC1, which impaired the function of CD8 + T cells and promoted their apoptosis. After downregulation of circ_0008287, in vivo tumorigenesis and metastasis were suppressed. ConclusionHence, this study suggests the promotive role of circ_0008287 in gastric cancer progression and immune escape and further elucidates the underlying circ_0008287/miR-548c-3p/CLIC1 regulatory axis.

Establishment and Preliminary Analysis of Lung Cancer Cell Line A549 with Stable MAP4 K4 Knockdown

To analyze the effect of knocking down MAP4 K4 expression on the proliferation and migration of cancer cells, and to explore its underlining molecular mechanisms. A stable knockdown MAP4 K4 cell line was constructed and the subcellular localization of the cells was determined with immunofluorescence, cell proliferation assay and cell migration assay. In addition, the effects of down-regulated MAP4 K4 expression were analyzed by examining the difference between the proliferation and migration of cancer cells in the knockdown group and those of the control group. MAP4 K4 was localized in focal adhesion and cell edges in A549 cells. Stable knockdown of MAP4 K4 expression induced cancer cells to grow in clusters and arrested the progression of the cell cycle and cell migration. Further analysis found that knocking down MAP4 K4 expression in A549 cells induced the accumulation of epithelial cell marker E-cadherin, and subsequently, the down-regulation of N-cadherin, a mesenchymal cell marker, thereby disrupting the "cadherin switch" and the epithelial-mesenchymal conversion. Then, the control group and the knockdown group both received the combined treatment of cisplatin at a final concentration of 5 μmol/L and paclitaxel at a final concentration of 20 nmol/L. The stably knocked down MAP4 K4 expressing cells showed significantly enhanced toxicity of chemotherapeutic drugs to cancer cells. The study shows that MAP4 K4 regulates the malignant phenotypes of cancer cells and chemoresistance by regulating "cadherin switch" to promote epithelial-mesenchymal transition in A549 cells.

Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9.

The axon guidance gene family, SLIT/ROBO pathway, controls neural network formation, which correlates with the development of several cancers. We found through analysis of the public database that ROBO4, one of the axon guidance molecules among the SLIT/ROBO family, is significantly downregulated in primary pancreatic cancer tissues compared with adjacent normal tissues. We carried out transfection experiments using three pancreatic cancer cell lines (MiaPaCa-2, BxPC-3, and SW1990) and one pancreatic duct epithelial cell line (HPDE6c7). A total of 51 clinical samples were then examined by immunohistochemical staining to find an association between ROBO4 expression at the protein level, clinical characteristics, and surgical outcomes. ROBO4 overexpression suppressed the invasion and migration abilities in MiaPaCa-2 and BxPC-3, while ROBO4 siRNA transfection to SW1990 and HPDE6c7 enhanced those activities. PCR-based profiling detected MMP-9 as a candidate downstream target of ROBO4, which was validated by decreased MMP-9 activity after the ROBO4 overexpression assay. High ROBO4 expression clinical samples had significantly better overall survival rather than low ROBO4 cases (P = 0.048). These findings suggest that decreased ROBO4 expression activates malignant phenotypes in cancer cells and is correlated with poor survival outcomes in pancreatic cancer.

Abstract 3644: Schwann cells reshape tumor cells and cancer associated fibroblasts in pancreatic ductal adenocarcinoma microenvironment

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by high degree of innervation and desmoplasia in its tumor microenvironment (TME). Nerves and cancer associated fibroblast (CAFs) represent two key components of TME. Schwann cells (SCs), the most prevalent cell type in peripheral nerves, have been reported to support neurons and facilitate neuronal guidance during repair, but their role and mechanism in PDAC development remain largely unknown. Cancer-associated fibroblasts (CAFs) are believed to be mainly responsible for desmoplasia in PDAC TME, but whether they are also involved in the regulation of SCs functions in PDAC is yet to be explored. Here, we aimed to illustrate the function and underlying mechanism of SCs in PDAC TME and verified its clinical relevance. Methods: We performed tissue microarray to evaluate the enrichment of SCs in tumors of different stages, as well as in adjacent normal tissues. Single cell RNA-sequencing (scRNA-seq) and microarray-based spatial transcriptomics (ST) were used to determine the interactions among SCs, tumor cells, and CAFs. We utilized co-culture and conditioned medium (CM) model to evaluate the role of SCs in reshaping TME. We employed intrasplenic injection model and patient-derived xenograft (PDX) mouse models to determine the role of SCs in tumor progression. To evaluate the differentiation of CAFs after SCs CM treatment, immunohistochemistry (IHC), immunofluorescence (IF), Western blot, enzyme-linked immunosorbent assay (ELISA), qPCR and bulk-RNA seq were performed. Mass spectrometry (MS), ELISA, and IF assays were also performed to identify the key regulators of SCs. Results: Significant neural hypertrophy and SCs infiltration were observed in tumor tissues and were associated with worse prognosis in PDAC patients. More cancer cells and CAFs could also be seen in proximity to SCs. scRNA-seq of PDAC samples demonstrated high degree of heterogeneity in both cancer cells and CAFs. We found a basal-like subgroup of cancer cells with more malignant behavior, and a pro-inflammatory subpopulation of CAFs (iCAFs) that promotes tumor progression. ST further showed that both basal-like cancer cells and iCAFs were located immediately adjacent to SCs in human PDAC tissues. The malignant phenotypes of cancer cells including migration, invasion, and proliferation were significantly promoted by SCs CM treatment. Furthermore, SCs CM treatment promotes iCAFs formation and PDAC progression in vitro and in vivo. Lastly, IL-1α was identified as a SCs-secreted ligand that generate iCAFs. Conclusion: Collectively, we find that SCs play an oncogenic role in PDAC by promoting the shift of cancer cells and CAFs toward more malignant phenotypes, and suggest that targeting SCs in TME represents a promising therapeutic strategy for PDAC treatment. Citation Format: Meilin Xue, Yongsheng Jiang, Lijie Han, Rui Su, Cheng Xiong, Youwei Zhu, Yizhi Cao, Minmin Shi, Jianjun Chen, Baiyong Shen, Lingxi Jiang, Hao Chen. Schwann cells reshape tumor cells and cancer associated fibroblasts in pancreatic ductal adenocarcinoma microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3644.

KCNN4 is a Potential Biomarker for Predicting Cancer Prognosis and an Essential Molecule that Remodels Various Components in the Tumor Microenvironment: A Pan-Cancer Study.

Objectives: Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) is a member of the KCNN family. Studies have revealed that KCNN4 is implicated in various physiological processes as well as promotes the malignant phenotypes of cancer cells. However, little is known about its associations with survival outcomes across varying cancer types. Methods: Herein, we systematically explored the prognostic value of KCNN4 in the pan-cancer dataset retrieved from multiple databases. Next, we performed correlation analysis of KCNN4 expression with tumor mutational burden (TMB) and microsatellite instability (MSI), and immune checkpoint genes (ICGs) to assess its potential as a predictor of immunotherapy efficacy. Afterwards, patients were divided into increased-risk group and decreased-risk group based on the contrasting survival outcomes in various cancer types. Furthermore, the underlying mechanisms of the distinctive effects were analyzed using ESTIMATE, CIBERSORT algorithms, and Gene Set Enrichment Analysis (GSEA) analysis. Results: KCNN4 expression levels were aberrant in transcriptomic and proteomic levels between cancer and normal control tissues in pan-cancer datasets, further survival analysis elucidated that KCNN4 expression was correlated to multiple survival data, and clinical annotations. Besides, KCNN4 expression was correlated to TMB and MSI levels in 14 types and 12 types of pan-cancers, respectively. Meanwhile, different types of cancer have specific tumor-infiltrating immune cell (TICs) profiles. Conclusions: Our results revealed that KCNN4 could be an essential biomarker for remodeling components in the tumor microenvironment (TME), and a robust indicator for predicting prognosis as well as immunotherapy response in pan-cancer patients.

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) family, are multifunctional cytokines. BMPs have a broad range of functions, and abnormalities in BMP signaling pathways are involved in cancer progression. BMPs activate the proliferation of certain cancer cells. Malignant phenotypes of cancer cells, such as increased motility, invasiveness, and stemness, are enhanced by BMPs. Simultaneously, BMPs act on various cellular components and regulate angiogenesis in the tumor microenvironment. Thus, BMPs function as pro-tumorigenic factors in various types of cancer. However, similar to TGF-β, which shows both positive and negative effects on tumorigenesis, BMPs also act as tumor suppressors in other types of cancers. In this article, we review important findings published in the recent decade and summarize the pro-oncogenic functions of BMPs and their underlying mechanisms. The current status of BMP-targeted therapies for cancers is also discussed.

APE1 shRNA-loaded cancer stem cell-derived extracellular vesicles reverse Erlotinib resistance in non-small cell lung cancer via the IL-6/STAT3 signalling.

ObjectiveApurinic endonuclease 1 (APE1) has been suggested as an oncogene of lung tumours and our bioinformatics analysis identified the association between Erlotinib resistance and interleukin‐6 (IL‐6). Thus, we performed this work to delineate the mechanistic actions of APE1/IL‐6 signalling in Erlotinib resistance of non‐small cell lung cancer (NSCLC).MethodsWe selected human NSCLC cell lines HCC827 and PC9 to establish Erlotinib‐resistant HCC827R and PC9R cells. Cancer stem cells (CSCs) were isolated from Erlotinib‐sensitive HCC827P and PC9P cells (PCSCs) and from HCC827R and PC9R cells (RCSCs). Further, extracellular vesicles (EVs) were separated from PCSCs (PCSC‐EVs) and RCSCs (RCSC‐EVs) and co‐cultured with RCSCs with or without short hairpin RNA (shRNA)‐targeting APE1 (APE1 shRNA) transduction. In addition, functional assays were conducted to determine the effect of APE1 shRNA on malignant phenotypes of cancer cells in vitro and in vivo and the activation of IL‐6/STAT3 signalling.ResultsIt was found that NSCLC cells could internalize both RCSC‐EVs and PCSC‐EVs. RCSC‐EVs augmented the resistance of NSCLC cells to Erlotinib. The overexpression of APE1 occurred in NSCLC tissues, and IL‐6 was enriched in serum samples of patients with NSCLC. APE1 shRNA was demonstrated to restrict the Erlotinib resistance of NSCLC cells by inactivating the IL‐6/STAT3 signalling. Additionally, shAPE1‐loaded RCSC‐EVs suppressed the Erlotinib resistance of NSCLC via the IL‐6/STAT3 axis both in vitro and in vivo, as reflected by impeded malignant phenotypes and xenograft tumour formation.ConclusionsCollectively, these data indicate that APE1 confers Erlotinib resistance by activating the IL‐6/STAT3 signalling, suggesting targeting APE1 as a possible therapeutic target in Erlotinib‐resistant NSCLC.