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1. High-fat circulating nutrients promote growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer

   https://doi.org/10.1101/2025.07.10.664224  

   Kohram, Maryam; Trenado-Yuste, Carolina; Brennan-Smith, Molly C; Navarro_Salazar, Evelyn S; Zhang, Pengfei; Hao, Jasmine E; Xu, Xincheng; Chavre, Bharvi; Oh, William; Zhang, Sherry X; et al (July 2025, bioRxiv)

   Abstract Diet influences the levels of small molecules that circulate in plasma and interstitial fluid, altering the biochemical composition of the tumor microenvironment (TME). These circulating nutrients have been associated with how tumors grow and respond to treatment, but it remains difficult to parse their direct effects on cancer cells. Here, we combine a three-dimensional (3D) microfluidic tumor model with physiologically relevant culture media to investigate how concentrations of circulating nutrients influence tumor growth, cancer cell invasion, and overall tumor metabolism. Human triple-negative breast cancer cells cultured in 2D under media conditions mimicking five different dietary states show no observable differences in proliferation or morphology. Nonetheless, those exposed to high-fat conditions exhibit increased metabolic activity and upregulate genes associated with motility and extracellular matrix remodeling. In the 3D microfluidic model, high-fat conditions accelerate tumor growth and invasion and induce the formation of hollow cavities. Surprisingly, the presence of these cavities does not correlate with an increase in apoptosis or ferroptosis. Instead, RNA-sequencing analysis revealed that high-fat conditions induce the expression ofMMP1, consistent with cavitation via cell invasion. Mimicking the flow of circulating nutrients within the TME can thus be used to identify novel connections between metabolic states and tumor phenotype. 

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2. MicroRNA-205-5p inhibits skin cancer cell proliferation and increase drug sensitivity by targeting TNFAIP8

   https://doi.org/10.1038/s41598-021-85097-6  

   Ge, Xinhong; Niture, Suryakant; Lin, Minghui; Cagle, Patrice; Li, P. Andy; Kumar, Deepak (December 2021, Scientific Reports)

   Abstract Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which regulates tumor growth and survival. Our goal is to delineate the detailed oncogenic role of TNFAIP8 in skin cancer development and progression. Here we demonstrated that higher expression of TNFAIP8 is associated with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma development in patient tissues. Induction of TNFAIP8 expression by TNFα or by ectopic expression of TNFAIP8 in SCC or melanoma cell lines resulted in increased cell growth/proliferation. Conversely, silencing of TNFAIP8 decreased cell survival/cell migration in skin cancer cells. We also showed that miR-205-5p targets the 3′UTR of TNFAIP8 and inhibits TNFAIP8 expression. Moreover, miR-205-5p downregulates TNFAIP8 mediated cellular autophagy, increased sensitivity towards the B-RAF V600E mutant kinase inhibitor vemurafenib, and induced cell apoptosis in melanoma cells. Collectively our data indicate that miR-205-5p acts as a tumor suppressor in skin cancer by targeting TNFAIP8. 

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3. Galactokinase 1 Inhibition-Induced Cell Cycle Arrest and Apoptosis in Bladder Cancer Cells Is Associated with AKT Signaling Downregulation

   https://doi.org/10.3390/ijms27062911  

   Singh, Surya P; Liu, Ronghao; Yan, Feng; Tang, Qinggong; Rao, Chinthalapally V; Madka, Venkateshwar (March 2026, International Journal of Molecular Sciences)

   Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease. 

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4. The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells

   https://doi.org/10.1038/s42003-023-04444-7  

   Noyes, Christopher; Kitajima, Shunsuke; Li, Fengkai; Suita, Yusuke; Miriyala, Saradha; Isaac, Shakson; Ahsan, Nagib; Knelson, Erik; Vajdi, Amir; Tani, Tetsuo; et al (December 2023, Communications Biology)

   Abstract Human cancers often re-express germline factors, yet their mechanistic role in oncogenesis and cancer progression remains unknown. Here we demonstrate that DEAD-box helicase 4 (DDX4), a germline factor and RNA helicase conserved in all multicellular organisms, contributes to increased cell motility and cisplatin-mediated drug resistance in small cell lung cancer (SCLC) cells. Proteomic analysis suggests that DDX4 expression upregulates proteins related to DNA repair and immune/inflammatory response. Consistent with these trends in cell lines, DDX4 depletion compromised in vivo tumor development while its overexpression enhanced tumor growth even after cisplatin treatment in nude mice. Further, the relatively higher DDX4 expression in SCLC patients correlates with decreased survival and shows increased expression of immune/inflammatory response markers. Taken together, we propose that DDX4 increases SCLC cell survival, by increasing the DNA damage and immune response pathways, especially under challenging conditions such as cisplatin treatment. 

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5. Identification of condition-specific regulatory mechanisms in normal and cancerous human lung tissue

   https://doi.org/10.1186/s12864-022-08591-9  

   Hang, Yuqing; Burns, Josh; Shealy, Benjamin T.; Pauly, Rini; Ficklin, Stephen P.; Feltus, Frank A. (December 2022, BMC Genomics)

   Abstract Background Lung cancer is the leading cause of cancer death in both men and women. The most common lung cancer subtype is non-small cell lung carcinoma (NSCLC) comprising about 85% of all cases. NSCLC can be further divided into three subtypes: adenocarcinoma (LUAD), squamous cell carcinoma (LUSC), and large cell lung carcinoma. Specific genetic mutations and epigenetic aberrations play an important role in the developmental transition to a specific tumor subtype. The elucidation of normal lung versus lung tumor gene expression patterns and regulatory targets yields biomarker systems that discriminate lung phenotypes (i.e., biomarkers) and provide a foundation for the discovery of normal and aberrant gene regulatory mechanisms. Results We built condition-specific gene co-expression networks (csGCNs) for normal lung, LUAD, and LUSC conditions. Then, we integrated normal lung tissue-specific gene regulatory networks (tsGRNs) to elucidate control-target biomarker systems for normal and cancerous lung tissue. We characterized co-expressed gene edges, possibly under common regulatory control, for relevance in lung cancer. Conclusions Our approach demonstrates the ability to elucidate csGCN:tsGRN merged biomarker systems based on gene expression correlation and regulation. The biomarker systems we describe can be used to classify and further describe lung specimens. Our approach is generalizable and can be used to discover and interpret complex gene expression patterns for any condition or species. 

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