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Tongue Squamous Cell Carcinoma (TSCC) represents a significant subtype of malignant oral cancer, characterized by a heterogeneous tumor microenvironment (TME). The tongue, a complex muscular organ, naturally presents an initial microenvironment that is largely inhospitable to the initiation and progression of TSCC. However, advanced-stage TSCC exhibits a pronounced accumulation of cancer-associated fibroblasts (CAFs), indicative of a drastic microenvironmental transformation. In this study, through comprehensive analysis combining cell model assessments and single-cell RNA sequencing data from a 4-NQO-induced TSCC mouse model, along with a lineage tracing-in-transplant assay, we elucidate and confirm the process of transdifferentiation whereby tongue muscle cells (TMCs) convert into CAFs in the TSCC context. Furthermore, we demonstrate that targeting TSCC with an IL-17a inhibitor offers a viable strategy to inhibit the reprogramming of TMCs into CAFs. Additionally, our research also identifies four critical marker genes involved in the transdifferentiation of TMCs to CAFs, Thbs1, Crabp1, Ifi205, and Cxcl5. Collectively, these findings delineate a mechanism through which TSCC cells induce the transdifferentiation of TMCs into CAFs, thereby transforming the cancer-suppressive microenvironment of the tongue into one that is conducive to TSCC progression. Tongue Squamous Cell Carcinoma (TSCC) is a subtype of head and neck cancer with poor prognosis. Here, the authors show that TSCC influences the transdifferentiation of tongue muscle cells into cancer-associated fibroblasts, transforming the tumor microenvironment into a tumor-supporting microenvironment.

Tongue squamous cell carcinoma (TSCC), a subtype of head and neck squamous cell carcinoma, is characterized by frequent chemoresistance. Genetic mutations commonly observed in TSCC play a critical role in malignant progression; thus, elucidating their functional significance is essential for developing effective treatment strategies. To more accurately investigate the relationship between mutations and chemoresistance, we established low-passage TSCC cells, CTSC-1, obtained from a chemoresistant patient, and CTSC-2, from a treatment-naïve patient. Sanger sequencing revealed a specific TP53 mutation (Q331*) in CTSC-1, leading to the loss of the tetramerization and C-terminal regulatory domains. Notably, CTSC-1 cells harboring TP53-Q331* and CTSC-2 cells with TP53 knockout that have been engineered to ectopically express TP53-Q331* exhibit enhanced chemoresistance and increased cancer stem cell-like properties. Mechanistically, TP53-Q331* upregulates the expression of inhibitor of DNA binding 2 (ID2), which is crucial for maintaining the stemness of TSCC cells. Subsequently, ID2 activates the expression of nucleotide excision repair (NER) pathway-related genes ERCC4 and ERCC8, thereby enhancing the chemoresistance in TSCC. In conclusion, our study demonstrates that the TP53-Q331* mutation enhances TSCC chemoresistance through an ID2-mediated NER pathway, providing a potential prognostic marker and therapeutic target for TSCC chemotherapy resistance.

Background Tongue squamous cell carcinoma (TSCC) is a malignant oral cancer with unclear pathogenesis that shows a tendency for early-stage lymphatic metastasis. This results in a poor prognosis, with a low 5-year survival rate. Dietary sodium nitrite (NaNO 2 ) has proposed associations with disease, including cancer. However, a direct relationship between NaNO 2 and TSCC has not been established. Methods In vitro and in vivo assays were used to investigate the role of NaNO 2 in TSCC. Protein expression in TSCC specimens was detected by immunohistochemistry and immunofluorescence. The molecular mechanism was determined using RT-qPCR, western blot, RNA-seq, luciferase reporter assays, migration assays, and FACS analysis. More detail of methods can be found in the Materials and methods section. Results The data in this study showed that NaNO 2 did not initiate carcinogenesis in the tongue but improved the lymphatic metastatic potential of TSCC cells in the specified experimental period. During metastasis to lymph nodes, monocyte-macrophage markers were upregulated in TSCC cells, whereas keratin markers were downregulated. Specifically, expression of the CD68 gene was high in TSCC cells following NaNO 2 -induced TSCC phenotypic switching. These phenotypic changes were associated with activation of transcription factor cyclic-AMP response binding protein (CREB1), which directly targets CD68 transcription. Furthermore, blocking CREB1 activity either through gene knockout or specific inhibitor treatment decreased the migration ability of TSCC cells and suppressed CD68 expression. Conclusions Our findings highlight the role of NaNO2 in enabling macrophage mimicry in TSCC cells through the CREB1-CD68 signaling pathway, which promotes lymphatic metastasis. Shedding light on drivers of lymphatic metastasis in TSCC and providing a new perspective on dietary strategies to improve outcomes of patients with TSCC.

Tongue squamous cell carcinoma (TSCC) is a malignant oral cancer with unclear pathogenesis that shows a tendency for early-stage lymphatic metastasis. This results in a poor prognosis, with a low 5-year survival rate. Dietary sodium nitrite (NaNO ) has proposed associations with disease, including cancer. However, a direct relationship between NaNO and TSCC has not been established. In vitro and in vivo assays were used to investigate the role of NaNO in TSCC. Protein expression in TSCC specimens was detected by immunohistochemistry and immunofluorescence. The molecular mechanism was determined using RT-qPCR, western blot, RNA-seq, luciferase reporter assays, migration assays, and FACS analysis. More detail of methods can be found in the Materials and methods section. The data in this study showed that NaNO did not initiate carcinogenesis in the tongue but improved the lymphatic metastatic potential of TSCC cells in the specified experimental period. During metastasis to lymph nodes, monocyte-macrophage markers were upregulated in TSCC cells, whereas keratin markers were downregulated. Specifically, expression of the CD68 gene was high in TSCC cells following NaNO -induced TSCC phenotypic switching. These phenotypic changes were associated with activation of transcription factor cyclic-AMP response binding protein (CREB1), which directly targets CD68 transcription. Furthermore, blocking CREB1 activity either through gene knockout or specific inhibitor treatment decreased the migration ability of TSCC cells and suppressed CD68 expression. Our findings highlight the role of NaNO2 in enabling macrophage mimicry in TSCC cells through the CREB1-CD68 signaling pathway, which promotes lymphatic metastasis. Shedding light on drivers of lymphatic metastasis in TSCC and providing a new perspective on dietary strategies to improve outcomes of patients with TSCC.

Cancer heterogeneity has been proposed to be one of the main causes of metastatic dissemination and therapy failure. However, the underlying mechanisms of this phenomenon remain poorly understood. Melanoma is an aggressive malignancy with a high heterogeneity and metastatic potential. Therefore, the present study investigated the possible association between cancer heterogeneity and metastasis in melanoma. In total, two novel Chinese oral mucosal melanoma (COMM) cell lines, namely COMM-1 and COMM-2, were established for exploring methods into preventing the loss of cellular heterogeneity caused by long-term cell culture. Each cell line was grown under two different models of culture, which yielded two subtypes, one exhibited an adhesive morphology (COMM-AD), whereas the other was grown in suspension (COMM-SUS). Compared with the COMM-AD cells, the COMM-SUS cells exhibited higher metastatic capacities and autofluorescence. Further investigations indicated that the COMM-SUS cells exhibited metabolic reprogramming by taking up lactate produced by COMM-AD cells at increased levels to accumulate NADH through monocarboxylate transporter 1, whilst also increasing NADPH levels through the pentose phosphate pathway (PPP). Additionally, increased NADH and NADPH levels in the COMM-SUS cells, coupled with the upregulation of the anti-ferroptotic proteins, glutathione peroxidase 4 and ferroptosis suppressor protein 1, enabled them to resist ferroptotic cell death induced by oxidative stress during hematogenous dissemination. The inhibition of ferroptosis was found to substantially increase the metastatic capacity of COMM-AD cells. Furthermore, suppressing lactate uptake and impairing PPP activation significantly decreased the metastatic potential of the COMM-SUS cells. Thus, the present study on metabolic heterogeneity in COMM cells potentially provides a novel perspective for exploring this mechanism underlying cancer metastasis.

Marrow niches in osteosarcoma (OS) are a specialized microenvironment that is essential for the maintenance and regulation of OS cells. However, existing animal xenograft models are plagued by variability, complexity, and high cost. Herein, we used a decellularized osteosarcoma extracellular matrix (dOsEM) loaded with extracellular vesicles from human bone marrow-derived stem cells (hBMSC-EVs) and OS cells as a bioink to construct a micro-osteosarcoma (micro-OS) through 3D printing. The micro-OS was further combined with a microfluidic system to develop into an OS-on-a-chip (OOC) with a built-in recirculating perfusion system. The OOC system successfully integrated bone marrow niches, cell‒cell and cell–matrix crosstalk, and circulation, allowing a more accurate representation of OS characteristics in vivo. Moreover, the OOC system may serve as a valuable research platform for studying OS biological mechanisms compared with traditional xenograft models and is expected to enable precise and rapid evaluation and consequently more effective and comprehensive treatments for OS. Schematic diagram showing the marrow-inspired OOC system could intimate bone marrow niches, cell-cell/cell-matrix crosstalk, and circulation, allowing for a more accurate portrayal of OS characteristics and drug responses in vivo. [Display omitted] •The significance of this study is demonstrated by the following aspects: (1) First, the decellularized osteosarcoma extracellular matrix (dOsEM) loaded with extracellular vesicles of bone marrow-derived stem cells (BMSC-EVs) was designed as an acellular bioink to construct a micro-osteosarcoma (micro-OS) for the expansion of biopsy samples and to maintain the biological features of OS tissue. (2) An OS-on-a-chip (OOC) system was established from the micro-OS combined with microfluidics, which imitated bone marrow niches, cell-cell and cell-matrix crosstalk, and circulation, allowing for a more accurate portrayal of OS characteristics in vivo. (3) The OOC system revealed that marrow niches regulated OS pathological processes and could serve as potential targets for OS treatment in the future.

Articular cartilage damage, an important cause of osteoarthritis (OA), is often caused by a senescent cartilage microenvironment and insufficient repair of chondrocytes. These effects are due to limited availability and a depleted stemness phenotype of chondrocyte stem cells, leading to the failure of cartilage repair and exacerbation of symptoms. In this study, a biomimetic gradient-structured cartilage organoid (BGSC-organoid) culture system was developed using decellularized cartilage extracellular matrix infused with extracellular vesicles from SOX9-overexpressing bone marrow-derived stem cells (SBEVs) to induce the rejuvenation of senescent chondrocytes. Single-cell sequencing revealed that a subpopulation of chondrocytes could be rejuvenated in the BGSC-organoid culture system. Moreover, an ex vivo osteoarthritis-on-a-chip (OAOC) model with cyclic mechanical stimulation was constructed to simulate the mechanical microenvironment of cartilage. BGSC-organoids exhibited sustained release of chondrocyte-protective factors and good mechanical resistance through the Vimentin/14-3-3/FOXO3 pathway. Animal studies showed that BGSC-organoids preserved a hyaline-like cartilage phenotype in vivo and delayed the degeneration of articular cartilage and intervertebral discs. Efficient expansion of human cartilage organoids with enhanced regenerative capabilities represents a promising approach for joint regeneration. Schematic diagram of the construction of the biomimetic gradient-structured cartilage organoid (BGSC-organoid) culture system and its application for maintaining the biological features of the cartilage niche and rejuvenating senescent chondrocytes. [Display omitted] •An osteoarthritis-on-a-chip (OAOC) model with cyclic mechanical stimulation was constructed to simulate the mechanical microenvironment of the joint capsule. BGSC-organoids exhibited good mechanical resistance and good sustained release capability for chondrocyte-protective factors ex vivo.•We further revealed the pharmacokinetic characteristics of BGSC-organoids ex vivo through the OAOC system. We verified that the BGSC-organoid culture system could maintain the biological features of the cartilage niche and rejuvenate senescent chondrocytes.•We demonstrated the therapeutic potential of BGSC-organoids in vivo in the context of intervertebral disc degeneration and OA, which are two major orthopedic diseases involving cartilage degeneration caused by mechanical environment changes.

Background: The liver metastasis accompanied with the loss of liver function is one of the most common complications in patients with triple-negative breast cancers (TNBC). Lineage reprogramming, as a technique direct inducing the functional cell types from one lineage to another lineage without passing through an intermediate pluripotent stage, is promising in changing cell fates and overcoming the limitations of primary cells. However, most reprogramming techniques are derived from human fibroblasts, and whether cancer cells can be reversed into hepatocytes remains elusive. Methods: Herein, we simplify preparation of reprogramming reagents by expressing six transcriptional factors (HNF4A, FOXA2, FOXA3, ATF5, PROX1, and HNF1) from two lentiviral vectors, each expressing three factors. Then the virus was transduced into MDA-MB-231 cells to generated human induced hepatocyte-like cells (hiHeps) and single-cell sequencing was used to analyze the fate for the cells after reprogramming. Furthermore, we constructed a Liver-on-a-chip (LOC) model by bioprinting the Gelatin Methacryloyl hydrogel loaded with hepatocyte extracellular vesicles (GelMA-EV) bioink onto the microfluidic chip to assess the metastasis behavior of the reprogrammed TNBC cells under the 3D liver microenvironment in vitro. Results: The combination of the genes HNF4A, FOXA2, FOXA3, ATF5, PROX1 and HNF1A could reprogram MDA-MB-231 tumor cells into human-induced hepatocytes (hiHeps), limiting metastasis of these cells. Single-cell sequencing analysis showed that the oncogenes were significantly inhibited while the liver-specific genes were activated after lineage reprogramming. Finally, the constructed LOC model showed that the hepatic phenotypes of the reprogrammed cells could be observed, and the metastasis of embedded cancer cells could be inhibited under the liver microenvironment. Conclusion: Our findings demonstrate that reprogramming could be a promising method to produce hepatocytes and treat TNBC liver metastasis. And the LOC model could intimate the 3D liver microenvironment and assess the behavior of the reprogrammed TNBC cells.