Metastatic Cell Research Articles

WTAP-dependent N6-methyladenosine methylation of lncRNA TEX41 promotes renal cell carcinoma progression.

The methyltransferase Wilms' tumor 1-associated protein (WTAP) has been reported to be dysregulated in various tumors. However, its role in renal cell carcinoma (RCC) remains elusive. Here, we explored whether WTAP was upregulated in RCC specimens compared to normal tissues. Functionally, WTAP promoted RCC cell proliferation and metastasis in vivo and in vitro. Mechanistically, WTAP act as an N6-methyladenosine transferase to regulate the m6A modification of long noncoding RNA TEX41. Then, the upregulated m6A modification destabilized TEX41 in a YTHDF2-dependent manner. Furthermore, TEX41 interacted with the SUZ12 protein and increased the histone methyltransferase activity of SUZ12, resulting in HDAC1 silencing. Totally, our study demonstrated the oncogenic the role of WTAP/TEX41/SUZ12/HDAC1 axis in RCC progression.

Severe hypersensitivity reactions to 2 immunotherapy agents in a patient with cutaneous squamous cell carcinoma.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. There is currently limited data on cross-sensitivity between immunotherapy agents. In this case study, we report a case of severe anaphylaxis to both pembrolizumab and cemiplimab. Pembrolizumab (Keytruda) and cemiplimab (Libtayo) are both approved for the treatment of metastatic cutaneous squamous cell carcinoma. Infusion reactions occur rarely with immunotherapy agents. However, if infusion reactions are severe, the treatment should be discontinued, and there is no guidance as to whether another immunotherapy agent may be used. An 87-year-old-male was diagnosed with metastatic cutaneous squamous cell carcinoma expressing a PD-L1 combined positive score of 81%-90%. He was treated with pembrolizumab and, 15 minutes after completion of the first infusion, developed swelling of the eyelids, ears, and tongue in addition to a whole-body rash without pruritus. Due to the severity of the reaction, pembrolizumab was permanently discontinued and the patient was then started on cemiplimab. The patient received a high-dose corticosteroid as premedication before the first infusion of cemiplimab and tolerated the treatment without any adverse effects. However, when the corticosteroid premedication dose was decreased before the second cycle, the patient had a severe infusion reaction to cemiplimab requiring discontinuation. A patient with metastatic cutaneous squamous cell carcinoma developed a severe hypersensitivity reaction to pembrolizumab and subsequently to cemiplimab, despite premedication.

SEC14L3 knockdown inhibited clear cell renal cell carcinoma proliferation, metastasis and sunitinib resistance through an SEC14L3/RPS3/NFκB positive feedback loop

BackgroundClear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive.MethodsBy leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays.ResultsOur investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth.ConclusionOur findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.

Immunohistochemical expression of ephrin receptors in neuroendocrine neoplasms: a case-series of gastroenteropancreatic neuroendocrine neoplasms and a systematic review of the literature.

Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of tyrosine kinases receptors (TKR) in humans, implicated in cell proliferation, adhesion, migration, tumor angiogenesis, invasion and metastasis. The aim of the present study is to assess the expression of EPHs in neuroendocrine neoplasms (NENs). Immunohistochemical staining of specimens of 30 patients with gastroenteropancreatic and lung NENs was performed for EPH-A1, EPH-A2, EPH-A4, EPH-A5 protein expression, in addition to ki-67 multiplication index and programmed death-ligand 1. Additionally, we performed a systematic review of the available literature in three different databases reporting on the expression of EPH in all neuroendocrine neoplasms. Positive expression was seen in 16/19 (84%) specimens for EPH-A1, 15/23 (65%) for EPH-A2, 21/24 (88%) for EPH-A4, 24/26 (92%) for EPH-A5. EPH-A1 was expressed in 9/9 pancreatic, 3/4 small intestine, but not in one lung NEN, EPH-A2 in 5/10 pancreatic, 3/4 small intestine and lung, and in one of each of gastric, appendix, colorectal, and cervical NENs, respectively. EPH-A4 showed positive expression in 9/11 pancreatic, 4/4 small intestine, 3/3 lung specimens and EPH-A5 in 10/11, 4/4 and 4/4, respectively. Data retrieved from the systematic review of the literature in combination with the data from the present study are suggestive of a frequent EPH expression in pituitary, thyroid, lung and gastroenteropancreatic NENs, yet, with varying expressions of the single receptor subtypes. EPHs may have a role in NEN tumorigenesis, prognosis as well as a role in the evolving molecular-targeted therapies.

The Large GTPase Guanylate-Binding Protein-1 (GBP-1) Promotes Mitochondrial Fission in Glioblastoma.

Glioblastomas (aka Glioblastoma multiformes (GBMs)) are the most deadly of the adult brain tumors. Even with aggressive treatment, the prognosis is extremely poor. The large GTPase Guanylate-Binding Protein-1 (GBP-1) contributes to the poor prognosis of GBM by promoting migration and invasion. GBP-1 is substantially localized to the cytosolic side of the outer membrane of mitochondria in GBM cells. Because mitochondrial dynamics, particularly mitochondrial fission, can drive cell migration and invasion, the potential interactions between GBP-1 and mitochondrial dynamin-related protein 1 (Drp1) were explored. Drp1 is the major driver of mitochondrial fission. While GBP-1 and Drp1 both had punctate distributions within the cytoplasm and localized to regions of the cytoplasmic side of the plasma membrane of GBM cells, the proteins were only molecularly co-localized at the mitochondria. Subcellular fractionation showed that the presence of elevated GBP-1 promoted the movement of Drp1 from the cytosol to the mitochondria. The migration of U251 cells treated with the Drp1 inhibitor, Mdivi-1, was less inhibited in the cells with elevated GBP-1. Elevated GBP-1 in GBM cells resulted in shorter and wider mitochondria, most likely from mitochondrial fission. Mitochondrial fission can drive several important cellular processes, including cell migration, invasion, and metastasis.

Tetrahedral Framework Nucleic Acid-Loaded Retinoic Acid Promotes Osteosarcoma Stem Cell Clearance.

Metastatic osteosarcoma is a commonly seen malignant tumor in adolescents, with a five year survival rate of approximately 20% and a lack of treatment options. Osteosarcoma cancer stem cells are considered to be important drivers of the metastasis of osteosarcoma, and therefore their clearance is considered a promising strategy for treating metastatic osteosarcoma. In the relevant literature, retinoic acid (ATRA) is considered effective for eliminating osteosarcoma stem cells, but it has some inherent disadvantages, including poor solubility, difficulty in entering cells, and structural instability. Tetrahedral framework nucleic acids (tFNAs) are a type of nanoparticles that can carry small-molecule drugs into cells to exert therapeutic effects. Therefore, we designed and synthesized a nanoparticle named T-ATRA by using tFNAs to load ATRA and studied its effect in a nude mouse model. T-ATRA is more effective than ATRA in the clearance of osteosarcoma stem cells and in inhibiting osteosarcoma cell metastasis via the Wnt signaling pathway, thus prolonging the survival time of nude mice with osteosarcoma.

SERPINA1 promotes the invasion, metastasis, and proliferation of pancreatic ductal adenocarcinoma via the PI3K/Akt/NF-κB pathway

Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells in vitro and in vivo. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.

Abstract A048: The Loss of Cholesterol Efflux Pump ABCA1 Skews Macrophages Towards a Pro-tumor Phenotype and Facilitates Breast Cancer Progression

Abstract Breast cancer is the most common and second-leading cause of cancer-related fatalities in women in the United States. The primary cause of mortality is often the recurrence of metastatic breast cancer. While immunotherapy shows some effectiveness, it has only been approved for patients who stain positive for PD-L1. Previous research in our lab has shown that macrophage function can be regulated through disruption in cholesterol metabolism. Additionally, elevated plasma cholesterol levels have been associated with breast cancer recurrence. These findings underscore the impact of cholesterol homeostasis in tumor-associated macrophages on breast cancer progression. An in-depth computational screen helped us pinpoint ABCA1—a cholesterol efflux protein whose elevated mRNA expression linked to increased survival. In addition to efflux, ABCA1 can also translocate cholesterol from the inner leaflet of the plasma membrane to the outer layer. Highlighting the clinical importance of ABCA1 are our findings that show that increased ABCA1 levels within breast tumors correlate to an increase in cytotoxic T Cells, and T cell effector enzymes (Prf-1 and Gzmb), and improved survival rates. Importantly, our in vitro studies suggest that ABCA1 influences several functions of macrophages relevant to tumor biology. Specifically, ABCA1 shifts macrophages towards an anti-cancer phenotype by (1) increasing their ability to infiltrate tumor spheroids, (2) decreasing angiogenesis, (3) decreasing efferocytosis—an immune-suppressive phagocytic process devoid of antigen presentation, and (4) enhancing the expansion, migration, and activity of cytotoxic T cells. The culmination of these attributes were demonstrated by our observations that syngeneic grafts of E0771 mammary tumors grew at an accelerated rate in mice with a myeloid-specific knockout of ABCA1 (ABCA1fl/fl;LysMcre+) compared to control mice. ABCA1 transports cholesterol from macrophages to a lipid-poor ApoA1 protein and facilitates the formation of nascent HDL via the reverse cholesterol transport pathway. We leveraged this mechanism to therapeutically target ABCA1 using ApoA1 mimetics 5A and 4F. Our data so far indicates that ApoA1 mimetics phenocopy ABCA1 overexpression skewing macrophages towards an anti-tumor phenotype. Importantly, treatment with 5A in mice grafted with 4T1 metastatic breast cancer cell line resulted in marked reduction in tumor burden. Additionally, we observed an increased infiltration of cytotoxic T cells and a decrease in CD31 expression, suggesting reduced blood vessel formation. Collectively, our data strongly supports the role of ABCA1 in the development of breast cancer. The expected results from this research will lay the groundwork for future therapeutic strategies for the use of ABCA1 and ApoA1 mimetics in the treatment of breast cancer. Citation Format: Shruti Bendre, Natalia Krawczynska, Shaunak Bhogale, Erin Weisser, Simon Han, Basel Hajyousif, Avni Singh, Rajendra KC, Yu Wang, Claire P Schane, Adam T Nelczyk, Dhanya Pradeep, Lara Kockaya, Hashni Epa Vidana Gamage, Kevin VanBortle, Emad Tajkorshid, Saurabh Sinha, Wendy A Woodward, Wonhwa Cho, Erik R Nelson. The Loss of Cholesterol Efflux Pump ABCA1 Skews Macrophages Towards a Pro-tumor Phenotype and Facilitates Breast Cancer Progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A048.

Abstract B005: Denosumab Enhances Cytotoxic T Cell Infiltration by supressing SPP1 Expression in Giant Cell Tumour of Bone

Abstract Denosumab, a RANKL inhibitor, is primarily used to prevent osteoclastogenesis for the treatment of conditions like osteoporosis, bone metastasis, and giant cell tumor of bone (GCTB). RANKL is also key in immunity, activating NFκB and its target genes, including the osteopontin-coding gene SPP1, which is linked with CXCL9:SPP1 macrophage polarization and prognosis. Retrospective studies of bone metastasis have demonstrated improved clinical outcomes when immune checkpoint inhibitors (ICIs) are combined with denosumab. We undertook a study to explore denosumab's direct role in anti-tumor immunity. Single-cell RNA sequencing was performed on nine primary human GCTB samples, including three untreated and six treated solely with denosumab, to exclude confounding treatment factors linked with bone metastasis samples. Furthermore, we utilized immunohistochemistry staining from paired pre- and post-denosumab treated samples from a cohort of nine GCTB patients and conducted pan-cancer analysis on primary tumors, spanning 31 distinct types of cancers, sourced from the Genomic Data Commons Data Portal. Our single-cell analysis of GCTB resulted in a comprehensive cell atlas of this rare disease, revealing denosumab's role in inhibiting SPP1 expression and augmenting cytotoxic T cell infiltration. This was confirmed in nine pairs of pre- and post-denosumab treated GCTB samples using immunohistochemistry staining. The pan-cancer analysis indicated a negative correlation between SPP1 expression and CD8A levels across most tumor types, with the CD8A/SPP1 ratio correlating with clinical outcomes in 14 cancer types. Our research provides robust clinical evidence that denosumab improves anti-tumor immunity by inhibiting SPP1 expression, presenting a significant step towards patient selection for combined ICI and denosumab therapy. Citation Format: Zezhuo Su, Maximus Chun Fai Yeung, Jason Pui Yin CHEUNG, Kelvin Sin Chi Cheung. Denosumab Enhances Cytotoxic T Cell Infiltration by supressing SPP1 Expression in Giant Cell Tumour of Bone [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B005.

Predictive markers of response to immune checkpoint inhibitor rechallenge in metastatic non-small cell lung cancer.

The present study aims to evaluate the efficacy of rechallenge with immune checkpoint inhibitors (ICIs) compared to chemotherapy and the predictive role of clinical parameters in non-small cell lung cancer (NSCLC) patients who were rechallenged. The study included 113 metastatic NSCLC patients who had initially responded to ICIs and platinum-based chemotherapy, either in combination in the first line or sequentially in the first and second line, but later experienced disease progression. Of those patients, 52 later received ICI rechallenge and 61 were exposed to chemotherapy. In the rechallenge cohort, the median age was 67 years, 38 patients were men (73.1%), 26 (50.0%) had squamous cell carcinoma. Patients who underwent ICI rechallenge had longer overall survival (OS) compared to those who received chemotherapy (12.9 months vs. 9.6 months, P = 0.008). Multivariate analysis for progression-free survival (PFS) and OS revealed that poor Eastern Cooperative Oncology Group Performance Status (ECOG PS; PFS: P = 0.013 and OS: P = 0.037), absence of objective response during initial ICI therapy (PFS: P = 0.014 and OS: P = 0.028), and baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P = 0.001 and OS: P = 0.003) were negative predictive factors of ICI rechallenge. The three parameters were included in a risk model named as the NEO score, which stratified patients who received ICI rechallenge into two predictive groups. Patients with ECOG PS 0-1, objective response during initial ICI treatment, and NLR < 3.8 (favorable group) had longer PFS (8.6 months vs. 3.0 months, P < 0.001) and OS (16.6 months vs. 5.5 months, P < 0.001) compared to those with absence of all three markers (poor group). There was no association between the NEO score and survival outcomes in patients who did not undergo rechallenge. ICI rechallenge showed a survival benefit, particularly in NSCLC patients with NLR < 3.8, good ECOG PS, and objective response.

Phase 1b Study of the Immunocytokine Simlukafusp alfa (FAP-IL2v), in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma.

This phase 1b trial evaluated FAP-IL2v, a novel immune-cytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC). Patients received FAP-IL2v either on a continuous weekly (QW) schedule, or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses. A total of 58 patients were enrolled, 19 patients into the dose-escalation, and 39 patients into the expansion part. The MTD of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v-related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode-of-action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, the objective response rate was 7% (95% CI: 3.2, 14.7). The safety profile of FAP-IL2v in combination with cetuximab was acceptable and pharmacodynamic markers support the proposed mode-of-action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).].

CircLPHN3 correlates with prognosis in colorectal cancer and regulates cellular processes by targeting miR-142-5p.

Colorectal cancer (CRC) is often diagnosed late and has a poor prognosis. Circular RNAs (circRNAs) have been identified as prognostic biomarkers in various cancers, including CRC. The objective was to elucidate the role of circLPHN3 (hsa_circ_0069865) in CRC progression and to provide a promising prognostic marker for CRC. CircLPHN3 was identified through bioinformatics analysis of the GSE121842 dataset. The levels of circLPHN3 in CRC samples were analyzed by real time-quantitative polymerase chain reaction. Its clinical significance was assessed using the Kaplan-Meier curve and multivariate Cox regression. Downstream microRNAs of circLPHN3 were predicted with the RNAhybrid, Circular RNA Interactome, and starBase online databases. The target of miR-142-5p was predicted using miRDB, TargetScanHuman, starBase, and miRWalk databases. The relationship between circLPHN3, miR-142-5p, and LDB2 was verified by dual luciferase reporter assay. The function of circLPHN3 on CRC cell growth and metastasis was measured using Transwell and the cell counting kit-8 assay. Significant downregulation of circLPHN3 was found in CRC. CircLPHN3 was closely related to higher tumor node metastasis stage, lymph node metastasis, and predicted unfavorable prognosis. miR-142-5p was highly expressed in CRC and its expression was negatively regulated by circLPHN3. Overexpression of circLPHN3 curbed CRC cell growth, migration, and invasion, mediated by miR-142-5p. Moreover, LDB2 was identified as a target of miR-142-5p. CircLPHN3 acted as a prognostic biomarker and tumor suppressor for CRC via modulating miR-142-5p.

CD73 promotes non–small cell lung cancer metastasis by regulating Axl signaling independent of GAS6

As catabolic enzyme, CD73 dephosphorylates adenosine monophosphate (AMP) and can also regulate tumor cell proliferation and metastasis. To date, very few studies have explored the role of CD73 in mediating non-small cell lung cancer (NSCLC) metastasis, and the underlying transducing signal has not been elucidated. In the present study, we demonstrated that the CD73/Axl axis could regulate Smad3-induced epithelial-to-mesenchymal transition (EMT) to promote NSCLC metastasis. Mechanically, CD73 can be secreted via the Golgi apparatus transport pathway. Then secreted CD73 may activate AXl by directly bind with site R55 located in Axl extracellular domain independently of GAS6. In addition, we proved that CD73 can stabilize Axl expression via inhibiting CBLB expression. We also identified the distinct function of CD73 activity in adenocarcinoma and squamous cell carcinoma. Our findings indicated a role of CD73 in mediating NSCLC metastasis and propose it as a therapeutic target for NSCLC.

OS10.4.A CXCL1 MEDIATES LEPTOMENINGEAL METASTASIS GROWTH

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer characterized by the entry of metastatic cancer cells originated from solid or hematologic tumors into the cerebrospinal fluid (CSF)-filled leptomeningeal compartment encasing the brain and the spinal cord. LM occurs in 5-20% in patients with solid tumors, especially those with breast cancer, lung cancer, melanoma. Untreated LM patients succumb within 4-6 weeks after diagnosis, or 2-5 months when they are treated with the current available therapies. To date, the only efficacious life-prolonging intervention was the application of proton craniospinal irradiation (pCSI) as demonstrated in the recent clinical trial, NCT04343573, with an average overall survival of 9 months. While a cohort of pCSI-treated patients survived over 18 months (responders), another cohort did not respond to pCSI and succumbed to the disease within 3 months post-treatment (non-responders). In this project, we aimed to characterize the molecular basis of pCSI response to turn the non-responders into responders. MATERIAL AND METHODS We performed proteomic analyses on serially collected CSF from LM patients at baseline (before pCSI), and multiple time points post-treatment. We further established syngeneic mouse models of LM-CSI to define the molecular basis of pCSI resistance. RESULTS We found that pCSI resulted in a significant drop in the levels of the chemokine CXCL1, a CXC-motif chemokine with elevated baseline levels after the onset of LM. Patients with significantly higher CSF CXCL1 levels prior to pCSI had worse central nervous system (CNS) progression-free survival. Using our preclinical LM mouse models, we found that both the cancer and host cells, namely macrophages, choroid plexus epithelial cells, and leptomeningeal fibroblasts, were a source of CXCL1. Genetic manipulation of Cxcl1expression in cancer cells or host revealed that the CXCL1 produced by the cancer cells was an essential factor for their growth in the leptomeninges. Moreover, we found that a subset of cancer cells expressed a receptor for CXCL1 - CXCR2 - and transcriptomic profiling of this rare population revealed an enrichment in pathways associated with cell cycle progression. Finally, intrathecally delivered CXCR2 antagonist hampered the LM growth. CONCLUSION Our results indicate that CXCL1/CXCR2 signaling axis regulates LM growth and suggests interruption of this signaling axis as a possible actionable therapeutic intervention to halt LM progression.

N6-Methyladenosine Methyltransferase Component KIAA1429 Is a Potential Target of Cancer Therapy

N6-methyladenosine (m6A), the most abundant RNA modification in eukaryotes, has a crucial impact on tumorigenesis. KIAA1429 is the key component of the m6A methyltransferase complex, in which KIAA1429 functions as a scaffold to bridge the catalytic core proteins. KIAA1429 is often overexpressed in malignances, associated with patient prognosis, and required for tumorigenesis. KIAA1429 regulates the expression of a number of tumor-associated genes in an m6A -dependent manner, and thus, contributes to cell proliferation, migration, drug resistance, tumor formation and metastasis. This review focuses on recent progress in the understanding of roles and mechanisms of KIAA1429 in cancers, and offers ideas for potential anti-cancer therapeutic methods by targeting KIAA1429.

Exploring the Dual Role of MALAT1 in Thyroid Tumorigenesis: Oncogenic or Tumor Suppressor?

Thyroid cancer is the most prevalent form of endocrine cancer. Therefore, the administration of new therapeutic agents for thyroid cancer patients is necessary. One of the recent successes in thyroid cancer research is the identification of the role of signaling pathways in the pathogenesis of the disease. Emerging evidence reveals that long non-coding RNAs (lncRNAs) can serve as novel therapeutic approaches for the diagnosis and treatment of thyroid cancer. The lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) plays key roles in gene expression, RNA processing, and epigenetic regulation. It is believed that MALAT1 can regulate several cancer-related processes, including tumour cell growth, proliferation, and metastasis. MALAT1 is involved in the pathogenesis of thzroid cancers by targeting multiple downstream targets and miRNA/mRNA axes. Here, we summarize the emerging roles of MALAT1 in this cancer.

Choline ameliorates tris (2‐chloroisopropyl) phosphate‐induced hepatocellular carcinoma metastasis by inhibiting ROS/Nrf2/Keap1‐mediated autophagy

AbstractTris (2‐chloroisopropyl) phosphate (TCPP) is an emerging environmental pollutant associated with liver diseases. However, its effects on hepatocellular carcinoma (HCC) remain unknown. Choline, a necessary dietary nutrient, has previously demonstrated inhibitory effects on HCC. Therefore, elucidating the underlying mechanism of TCPP exposure on HCC development and investigating whether choline could mitigate these effects may improve the prognosis of HCC patients. In this study, we examined the tumor‐promoting effects of TCPP on HCC and explored the protective effects of choline. Our findings revealed that choline treatment attenuated the tumor‐promoting effects of TCPP exposure on HCC cells’ epithelial‐mesenchymal transition (EMT) and lung metastasis. Further investigation showed that TCPP exposure induced ROS production via NOX4 upregulation, while choline inhibited ROS generation, thereby mitigating the effects of TCPP on EMT and metastasis in HCC cells. Mechanistic analysis demonstrated that excessive ROS inhibited levels of Keap1, leading to upregulation and nuclear translocation of Nrf2, which promoted autophagy flux and accelerated EMT and metastasis of HCC cells. However, choline treatment significantly impaired TCPP‐induced autophagy by attenuating the ROS/Nrf2/Keap1 pathway. Overall, our data illustrate the adverse effects of TCPP on the malignant progression of HCC and suggest that choline may serve as a potential nutrient to counteract the tumor‐promoting effects of TCPP on HCC.

P1.09A.03 Concurrent Combination of EGFR-TKIs and Thoracic Radiation Therapy for Metastatic Non Small Cell Lung Cancer Patients

P1.09A.03 Concurrent Combination of EGFR-TKIs and Thoracic Radiation Therapy for Metastatic Non Small Cell Lung Cancer Patients

Solid pancreatic masses: What’s hidden beneath? Insights into rare pancreatic lesions

The diagnostic approach to solid pancreatic masses has significantly evolved from the era when a focal pancreatic mass was almost synonymous to pancreatic ductal adenocarcinoma, to a wide spectrum of pancreatic lesions, some of which have good prognosis. With the advent of advanced diagnostic tools, particularly refined imaging and tissue acquisition techniques, a broader spectrum of differential diagnoses has been recognized, encompassing conditions ranging from neuroendocrine tumors or inflammatory masses, to rare entities like metastatic clear cell sarcoma or solitary fibrous tumors. We herein discuss case reports of some rare pancreatic lesions, which were diagnosed by combining clinical and imaging features and endoscopic ultrasound-guided tissue sampling and confirmed on surgical specimens. Further reports on these rare pancreatic tumors will contribute to a better understanding of their pathogenesis and effective management.

Mesenchymal stromal cells as cancer promoters.

Mesenchymal stromal cells (MSCs) are important cellular constituents of tumor stroma that play an active role in tumor development. Complex interactions between MSCs and cancer promote tumor progression by creating a favorable milieu for tumor cell proliferation, angiogenesis, motility, invasion, and metastasis. The cellular heterogeneity, source of origin, diversity in isolation methods, culture techniques and model systems of MSCs, together with the different tumor subtypes, add to the complexity of MSC-tumor interactions. In this review, we discuss the mechanisms of MSC-mediated tumor promotion and evaluate cell-stromal interactions between cancer cells, MSCs, cells of the tumor microenvironment (TME), and the extracellular matrix (ECM). A more thorough understanding of tumor-MSC interactions is likely to lead to better cancer management.