Lung cancer is one of the most common and lethal malignant tumors. Currently, surgical resection is the most effective treatment for early-stage lung cancer, and often results in favorable recovery outcomes. Therefore, early detection and control of lung cancer occurrence, invasion and metastasis are crucial for improving patient survival rates. Identifying tumor markers for lung cancer plays a vital role in facilitating early detection and control of its progression. The GALNT family proteins are enzymes that regulate the initial step in mucin O-glycan synthesis. It has been revealed that the expression of polypeptide N-acetyl-galactosamine-transferase (GALNT) family members is dysregulated in various tumors, and is closely associated with tumorigenesis, tumor cell growth, metastasis, adhesion, and serves as an important early indicator of tumor development. The present review compiles and analyzes findings concerning the role of GALNT family proteins in regulating lung cancer, with the goals of elucidating their mechanisms in lung cancer occurrence and progression and providing insights for improving the prognosis and therapeutic treatment of patients with lung cancer.

Neutrophils are traditionally viewed as uncomplicated exterminators that arrive quickly at sites of infection, kill pathogens, and then expire. However, recent studies employing modern transcriptomics coupled with novel imaging modalities have discovered that neutrophils exhibit significant heterogeneity within organs and have complex functional roles ranging from tissue homeostasis to cancer and chronic pathologies. This has revised the view that neutrophils are simplistic butchers, and there has been a resurgent interest in neutrophils. The spleen was described as a granulopoietic organ more than 4 decades ago, and studies indicate that neutrophils are briefly retained in the spleen before returning to circulation after proliferation. Transcriptomic studies have discovered that splenic neutrophils are heterogeneous and distinct compared with those in blood. This suggests that a unique hematopoietic niche exists in the splenic microenvironment, i.e., capable of programming neutrophils in the spleen. During severe systemic inflammation with an increased need of neutrophils, the spleen can adapt by producing neutrophils through emergency granulopoiesis. In this review, we describe the structure and microanatomy of the spleen and examine how cells within the splenic microenvironment help to regulate splenic granulopoiesis. A focus is placed on exploring the increase in splenic granulopoiesis to meet host needs during infection and inflammation. Emerging technologies such as single-cell RNA sequencing, which provide valuable insight into splenic neutrophil development and heterogeneity, are also discussed. Finally, we examine how tumors subvert this natural pathway in the spleen to generate granulocytic suppressor cells to promote tumor growth.

Gastric cancer (GC) is one of the most common tumors; one of the reasons for its poor prognosis is that GC cells can resist normal cell death process and therefore develop distant metastasis. Cuproptosis is a novel type of cell death and a limited number of studies have been conducted on the relationship between cuproptosis-related genes (CRGs) in GC. The purpose of the present study was to establish a prognostic model of CRGs and provide directions for the diagnosis and treatment of GC. Transcriptome and clinical data of patients with GC were collected from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Single sample gene set enrichment analysis (GSEA) and the randomized forest method were used to establish the prognostic model. Kaplan-Meier survival curve, receiver operating characteristics diagram and a nomogram were used to evaluate the reliability of the model. GSEA and gene set variation analysis (GSVA) were used to examine enrichment pathways between high and low risk groups. Finally, immunohistochemical analysis was used to examine ephrin 4 (EFNA4) expression in GC samples and determine the prognosis of patients with GC based on the expression pattern of EFNA4. A group of 7 predictive models (RTKN2, INO80B, EFNA4, ELF2, MUSTN, KRTAP4, and ARHGEF40) was established which were correlated with CRGs. This model can be used as an independent prognostic factor to predict the prognosis of patients with GC. GSEA and GSVA results indicated that high risk patients with GC were mainly associated with the enrichment of ANGIOGENESIS and TGF_BETA_SIGNALING pathways. Finally, EFNA4 expression in GC was significantly higher than that in normal tissues, and patients with GC and high EFNA4 expression exhibited improved prognosis. In conclusion, the prognosis model based on CRGs could be used as the basis for predicting the potential prognosis of patients with GC and provide new insights for the treatment of GC.

As the mechanisms underlying tumorigenesis become better understood, the dynamic roles of cellular components of the tumor microenvironment, and their cross-talk with tumor cells, have come to light as key drivers of disease progression and have emerged as important targets of new cancer therapies. In the field of oncolytic virus (OV) therapy, stromal cells have been considered as potential barriers to viral spread, thus limiting virus replication and therapeutic outcome. However, new evidence indicates that intratumoral fibroblasts could support virus replication. We have demonstrated in a rat model of stromal-rich intrahepatic cholangiocarcinoma (CCA) that vesicular stomatitis virus (VSV) can be localized within intratumoral hepatic stellate cells (HSCs), in addition to tumor cells, when the virus was applied via hepatic arterial infusion. Furthermore, VSV was shown to efficiently kill CCA cells and activated HSCs, and co-culture of CCA and HSCs increased viral titers. Interestingly, this effect is also observed when each cell type is cultured alone in a conditioned medium of the other cell type, indicating that secreted cell factors are at least partially responsible for this phenomenon. Partial reduction in sensitivity to type I interferons was observed in co-culture systems, providing a possible mechanism for the increased viral titers. Together, the results indicate that targeting activated HSCs with VSV could provide an additional mechanism of OV therapy, which, until now has not been considered. Furthermore, these findings suggest that VSV is a potentially powerful therapeutic agent for stromal-rich tumors, such as CCA and pancreatic cancer, both of which are very difficult to treat with conventional therapy and have a very poor prognosis.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

BACKGROUND CERVUS ELAPHUS SIBIRICUS: (CES) has been traditionally used in Korean clinics to promote fracture healing based on its function of tonifying the kidneys and strengthening bones. However, experimental data supporting its efficacy are still insufficient. The aim of this study investigated the bone-union properties of CES in a femoral fracture animal model and its corresponding molecular mechanisms.

Fifty-four C57BL/6 male mice underwent femoral shaft fracture by Bonnarens and Einhorn's method, subsequently receiving a water extract of CES (200 mg/kg/day, daily) for 7 and 14 days. Safranin O staining and immunohistochemistry of the fracture region were conducted against transforming growth factor-β (TGF-β), bone morphogenetic protein 2 (BMP2), and osterix. MG63 cells used to examine the underlying mechanisms of CES focused on BMP2-Smad pathway-related osteogenesis.

CES administration led to earlier union of the fractured bones, supported by Safranin O staining of the fracture region, demonstrating significantly increased cartilage formation day on 7 and a rapidly decreased cartilage area due to callus formation day on 14. CES administration also significantly upregulated the expression of TGF-β1 day 7, BMP 2, and osterix day 14 at the fracture site and also up-regulated alkaline phosphatase (ALP) activity, calcium deposition, and the phosphorylation of Smad in MG63 cells.

CES promotes fracture healing by promoting osteoblastogenesis via a partial BMP2-Smad pathway.

Emerging evidence indicates that intratumor bacteria exist as an active and specific tumor component in many tumor types beyond digestive and respiratory tumors. However, the biological impact and responsible molecules of such local bacteria-tumor direct interaction on cancer therapeutic response remain poorly understood. Trastuzumab is among the most commonly used drugs targeting the receptor tyrosine-protein kinase erbB-2 (ErbB2) in breast cancer, but its resistance is inevitable, severely limiting its clinical effectiveness. Here, we demonstrate that the quorum-sensing signaling molecule N-(3-oxo-dodecanoyl) homoserine lactone (3oc), a chemical compound released by Pseudomonas aeruginosa (P. aeruginosa), one tumor-resident bacteria with a relative high abundance in breast cancer, promotes breast cancer cell resistance to trastuzumab. Mechanically, 3oc directly leads to spontaneous dimerization of the transforming growth factor β (TGF-β) type II serine/threonine kinase receptor on the cell membrane in a ligand-independent manner. The 3oc-induced TGF-β signaling subsequently triggers ErbB2 phosphorylation and its downstream target activation, overcoming the inhibition effect of trastuzumab on ErbB2. With specific real-time qPCR, fluorescence in situ hybridization imaging, and liquid chromatography ionization tandem mass spectrometry analyses of clinical samples, we confirmed that P. aeruginosa and its signaling molecule 3oc exist in breast cancer tissues and there is a clinical correlation between P. aeruginosa colonization and trastuzumab resistance. This work expands the biological functions of intratumor bacteria in cancer treatment responsiveness and provides a unique perspective for overcoming trastuzumab resistance.

The primary node molecules in the cell signaling network in cancer tissues are maladjusted and mutated in comparison to normal tissues, which promotes the occurrence and progression of cancer. Pancreatic cancer (PC) is a highly fatal cancer with increasing incidence and low five-year survival rates. Currently, there are several therapies that target cell signaling networks in PC. However, PC is a "cold tumor" with a unique immunosuppressive tumor microenvironment (poor effector T cell infiltration, low antigen specificity), and targeting a single gene or pathway is basically ineffective in clinical practice. Targeted matrix therapy, targeted metabolic therapy, targeted mutant gene therapy, immunosuppressive therapy, cancer vaccines, and other emerging therapies have shown great therapeutic potential, but results have been disappointing. Therefore, we summarize the identified and potential drug-resistant cell signaling networks aimed at overcoming barriers to existing PC therapies.

The transforming growth factor β (TGF-β) signaling pathway exerts a dual role in oncogenesis, acting as a suppressor in healthy and early stage neoplastic tissues while promoting malignancy and metastasis in advanced cancers. Tumor hemorrhage further exacerbates TGF-β-mediated metastasis by up-regulating its expression. Here, a coagulation-targeting peptide (A15)-decorated TGF-β inhibitor nanomedicine (A15-LY-NPs) was developed. The tumor colonization assays showed that the nanomedicine reduced 4T1-luc cell colonization in normal tissues. When combined with a vascular disrupting agent, A15-LY-NPs demonstrated three times greater drug accumulation in the tumor at 24 h compared to the control and showed a 93.7% tumor suppression rate in 4T1 tumors initiated at ∼500 mm3, significantly attenuating metastatic spread to the lungs and liver. This study presents an innovative approach for the precise and efficient delivery of TGF-β inhibitors to tumors, offering the potential to augment the efficacy of cancer therapeutics.

HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We identify an αVβ6/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound αVβ6 recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between αVβ6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor-β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and αVβ6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive αVβ6-independent and HER2-independent tumor progression.

Transforming growth factor-β (TGFβ) and FoxP3 regulatory T cells (Treg) are involved in human breast carcinogenesis. This topic is not well documented in canine mammary tumors (CMT). In this work, the tumoral TGFβ expression was assessed by immunohistochemistry in 67 malignant CMT and its correlation to previously determined FoxP3, VEGF, and CD31 markers and other clinicopathologic parameters was evaluated. The high levels of TGFβ were statistically significantly associated with skin ulceration, tumor necrosis, high histological grade of malignancy (HGM), presence of neoplastic intravascular emboli and presence of lymph node metastases. The observed levels of TGFβ were positively correlated with intratumoral FoxP3 (strong correlation), VEGF (weak correlation) and CD31 (moderate correlation). Tumors that presented a concurrent high expression of TGFβ/FoxP3, TGFβ/VEGF, and TGFβ/CD31 markers were statistically significantly associated with parameters of tumor malignancy (high HGM, presence of vascular emboli and nodal metastasis). Additionally, shorter overall survival (OS) time was statistically significantly associated with tumors with an abundant TGFβ expression and with concurrent high expression of TGFβ/FoxP3, TGFβ/VEGF, and TGFβ/CD31. The presence of lymph node metastasis increased 11 times the risk of disease-related death, arising as an independent predictor of poor prognosis in the multivariable analysis. In conclusion, TGFβ and Treg cells seem involved in tumor progression emerging as potential therapeutic targets for future immunotherapy studies.

The TGF-β signaling pathway (TSP) is pivotal in tumor progression. Nonetheless, the connection between genes associated with the TSP and the clinical outcomes of breast cancer, as well as their impact on the tumor microenvironment and immunotherapeutic responses, remains elusive.

Breast cancer transcriptomic and single-cell sequencing data were obtained from the The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We identified 54 genes associated with the TSP from the Molecular Signatures Database (MSigDB) and analyzed both data types to evaluate TSP activity. Using weighted gene co-expression network analysis (WGCNA), we identified modules linked to TSP activity. To assess patient risk, we used 101 machine learning algorithms to develop an optimal TGF-β pathway-related prognostic signature (TSPRS). We then examined immune activity and response to immune checkpoint inhibitors and chemotherapy in these groups. Finally, we validated ZMAT3 expression levels clinically and confirmed its relevance in breast cancer using CCK-8 and migration assays.

At the single-cell level, TSP activity was most notable in endothelial cells, with higher activity in normal tissues compared to tumors. TSPRS was developed. This signature's accuracy was confirmed through internal and external validations. A nomogram incorporating the TSPRS was created to improve prediction accuracy. Further studies showed that breast cancer patients categorized as low-risk by the TSPRS had higher immune phenotype scores and more immune cell infiltration, leading to better prognosis and enhanced immunotherapy response. Additionally, a strong link was found between the TSPRS risk score and the effectiveness of anti-tumor agents. Silencing the ZMAT3 gene in the TSPRS significantly reduced the proliferation and invasiveness of breast cancer cells.

Our study developed a TSPRS, which emerges as a potent predictive instrument for the prognosis of breast cancer, offering novel perspectives on the immunotherapeutic approach to the disease.

Transforming Growth Factor β (TGFβ) is a pleiotropic cytokine closely linked to tumors. Previously, we pharmacologically inhibited basal nitric oxide (NO) production in healthy mammary glands and found that this induced precancerous progression accompanied by upregulation of TGFβ and desmoplasia. In the present study, we tested whether NO directly S-nitrosylates (forms an NO-adduct at a cysteine residue) TGFβ for inhibition, whereas reduction of NO denitrosylates TGFβ for de-repression. We introduced mutations to 3 C-terminal cysteines of TGFβ1 which were predicted to be S-nitrosylated. We found that these mutations indeed impaired S-nitrosylation of TGFβ1 and shifted the binding affinity towards the receptor from the latent complex. Furthermore, in silico structural analyses predicted that these S-nitrosylation-defective mutations strengthen the dimerization of mature protein, whereas S-nitrosylation-mimetic mutations weaken the dimerization. Such differences in dimerization dynamics of TGFβ1 by denitrosylation/S-nitrosylation likely account for the shift of the binding affinities toward the receptor versus latent complex. Our findings, for the first time, unravel a novel mode of TGFβ regulation based on S-nitrosylation or denitrosylation of the protein.

Morphogen gradients instruct cells to pattern tissues. Although the mechanisms by which morphogens transduce chemical signals have been extensively studied, the roles and regulation of the physical communication between morphogen-receiver cells remain unclear. Here, we show that the Wnt/β-catenin-morphogen gradient, which patterns the embryonic anterior-posterior (AP) axis, generates intercellular tension gradients along the AP axis by controlling membrane cadherin levels in zebrafish embryos. This "mechano-gradient" is used for the cell competition-driven correction of noisy morphogen gradients. Naturally and artificially generated unfit cells, producing noisy Wnt/β-catenin gradients, induce local deformation of the mechano-gradients that activate mechanosensitive calcium channels in the neighboring fit cells, which then secrete annexin A1a to kill unfit cells. Thus, chemo-mechanical interconversion-mediated competitive communication between the morphogen-receiver cells ensures precise tissue patterning.

Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.

This review concerns nc886, a 101-nucleotide non-coding RNA (ncRNA). Because nc886 is transcribed by RNA polymerase III (Pol III) and contains a CpG island in its promoter region, its expression is regulated by several transcription factors and the DNA methylation status. These features drive nc886 expression in two opposing directions during tumorigenesis. The known function of nc886 is to bind to and modulate the activity of target proteins such as PKR, Dicer, and OAS1. By being differentially expressed during tumorigenesis and interacting with these proteins, nc886 plays a role in tumor surveillance, promotes or suppresses tumorigenesis, and influences the efficacy of cancer therapy. The multiple roles of nc886 have been well-documented in the literature. In this review, we have summarized this literature and critically discussed the roles and mechanisms of action of nc886 in various cancers.

The tumor microenvironment (TME) plays a crucial role in cancer progression and immune evasion, partially mediated by the activity of the TME-derived exosomes. These extracellular vesicles are pivotal in shaping immune responses through the transfer of proteins, lipids, and nucleic acids between cells, facilitating a complex interplay that promotes tumor growth and metastasis. This review delves into the dual roles of exosomes in the TME, highlighting both their immunosuppressive functions and their emerging therapeutic potential. Exosomes can inhibit T cell function and promote tumor immune escape by carrying immune-modulatory molecules, such as PD-L1, yet they also hold promise for cancer therapy as vehicles for delivering tumor antigens and costimulatory signals. Additionally, the review discusses the intricate crosstalk mediated by exosomes among various cell types within the TME, influencing both cancer progression and responses to immunotherapies. Moreover, this highlights current challenges and future directions. Collectively, elucidating the detailed mechanisms by which TME-derived exosomes mediate T cell function offers a promising avenue for revolutionizing cancer treatment. Understanding these interactions allows for the development of targeted therapies that manipulate exosomal pathways to enhance the immune system's response to tumors.

Aromatic caninurine formamase (AFMID) is an enzyme involved in the tryptophan pathway, metabolizing N-formylkynurenine to kynurenine. AFMID had been found significantly downregulated in clear cell renal cell carcinoma (ccRCC) in both tissue and urine samples. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction, and elevated fat deposition, it is unknown whether AFMID plays a role in tumorigenesis and the development of ccRCC. In the present study, AFMID overexpression had inhibitory effects for ccRCC cells, decreasing the rate of cell proliferation. Quantitative proteomics showed that AFMID overexpression altered cellular signaling pathways involved in cell growth and cellular metabolism pathways, including lipid metabolism and inositol phosphate metabolism. Further urine proteomic analysis indicated that cellular function dysfunction with AFMID overexpression could be reflected in the urine. The activity of predicted upregulators DDX58, TREX1, TGFB1, SMARCA4, and TNF in ccRCC cells and urine showed opposing change trends. Potential urinary biomarkers were tentatively discovered and further validated using an independent cohort. The protein panel of APOC3, UMOD, and CILP achieved an AUC value of 0.862 for the training cohort and 0.883 for the validation cohort. The present study is of significance in terms of highlighting various aspects of pathway changes associated with AFMID enzymes, discovering potential specific biomarkers for potential patient diagnosis, and therapeutic targeting.

A structural or functional cervix problem prevents a woman from carrying a full-term pregnancy, which leads to the disease known as cervical insufficiency. Cervical insufficiency is partially inherited, and in certain situations, variations in genes related to connective tissue metabolism may be involved. The main objective of this investigation was to describe the collagen type I alpha 1 chain (COL1A1) gene rs1800012 polymorphism and the transforming growth factor beta 1 (TGFB1) gene rs1800471 polymorphism in a cohort of patients suffering from cervical insufficiency. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays have been used to analyze the DNAs of 93 patients with cervical insufficiency and 103 healthy controls. The chi-square test was used for statistical analysis. There were significant differences in the genotype frequencies of the COL1A1 gene rs1800012 (G > T) and TGFB1 gene rs1800471 (G > C) polymorphisms between the patient and the control groups (p = 0.049 and p = 0.049, respectively). Also, the C allele of the TGFB1 rs1800471 polymorphism was significantly higher in the patient group than the control group (p = 0.016). Following clinical assessment, the COL1A1 rs1800012 polymorphism was found to be connected to the history of cerclage (p = 0.010). Additionally, the frequency of the TT/GG composite genotype of COL1A1 rs1800012/TGFB1 rs1800471 polymorphisms was significantly lower in the patient group than the control group (p = 0.049). The TT genotype of COL1A1 rs1800012 polymorphism was found to be protective against cervical insufficiency, while the C allele of TGFB1 rs1800471 polymorphism was found to predispose to the disease. It appears that the TT/GG composite genotype of COL1A1 rs1800012/TGFB1 rs1800471 polymorphisms protects against cervical insufficiency.

Over the past two decades, extensive studies, particularly in cancer analysis through large datasets like The Cancer Genome Atlas (TCGA), have aimed at improving patient therapies and precision medicine. However, limited overlap and inconsistencies among gene signatures across different cohorts pose challenges. The dynamic nature of the transcriptome, encompassing diverse RNA species and functional complexities at gene and isoform levels, introduces intricacies, and current gene signatures face reproducibility issues due to the unique transcriptomic landscape of each patient. In this context, discrepancies arising from diverse sequencing technologies, data analysis algorithms, and software tools further hinder consistency. While careful experimental design, analytical strategies, and standardized protocols could enhance reproducibility, future prospects lie in multiomics data integration, machine learning techniques, open science practices, and collaborative efforts. Standardized metrics, quality control measures, and advancements in single-cell RNA-seq will contribute to unbiased gene signature identification. In this perspective article, we outline some thoughts and insights addressing challenges, standardized practices, and advanced methodologies enhancing the reliability of gene signatures in disease transcriptomic research.

The primary cause of mortality in colorectal cancer (CRC) patients is tumor metastasis. The epithelial-mesenchymal transition (EMT) stands out as a crucial factor promoting the metastasis of CRC. Previous findings suggest a potential inhibitory effect of docosahexaenoic acid (DHA) on CRC metastasis, but the precise mechanism remains unknown, this study aims to explore this issue. We assessed metastasis and recurrence, all-cause mortality, and cancer-related mortality rates according to DHA intake in independent CRC cohorts (n = 367) by survival analysis. The ability of DHA to block CRC cell migration and invasion was tested using transwell and wound-healing assays. The regulation of EMT marker genes in CRC by DHA was detected by quantitative real-time PCR (qPCR) and immunoblotting, and the effect of DHA on the TGF-β1/Smad signaling pathway was further investigated. These cellular findings were validated using a subcutaneous CRC mouse model. Survival analyses showed that lower DHA intake was associated with a higher risk of CRC metastasis and a poorer prognosis. In vitro experiments showed that DHA inhibits the TGF-β1/Smad signaling pathway and regulates downstream transcription factors, thereby reversing the EMT and inhibiting invasion and migration. In the mouse model, dietary DHA supplementation effectively increased blood DHA concentrations and inhibited CRC metastasis. Our study demonstrated that DHA inhibits CRC invasion and metastasis by inhibiting the TGF-β1/Smad signaling pathway. Increased intake of DHA among CRC patients may provide additional benefits to the prognosis of colorectal cancer.

Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI).

A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot.

The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression.

Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa). USP11 expression was up-regulated in metastatic PCa and CRPC. USP11 knockdown (KD) significantly inhibited PCa cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 KD. ChIP-seq analysis showed that either USP11 KD or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to up-regulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability and deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc reexpression in USP11-KD PCa cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive PCa through upregulation of AR and c-Myc activities and support USP11 as a potential target against PCa.

Withanolides are a group of naturally occurring plant-based small molecules known for their wide range of host cellular functions. The anticancer potential of withanolides has been explored in varying cancer cell lines in vitro. Based on our prior studies, among the tested withanolides, withametelin (WM) has shown significant cytotoxicity with the highest efficacy on HCT-116 colon cancer cells (IC50 0.719 ± 0.12μM). Treatment with WM reduced the TGF-β driven proliferation, colony-forming ability, migration, and invasiveness of HCT-116 cells in vitro. WM also downregulated the expression of mesenchymal markers such as N-CADHERIN, SNAIL, and SLUG in HCT-116 cells. At the molecular level, WM inhibited TGF-β induced phosphorylation of SMAD2/3 and reduced the expression of an immune checkpoint inhibitor programmed-death ligand-1 (PD-L1). Our study highlights the possible anticancer mechanisms of WM involving modulation of the TGF-β pathway and associated target gene expression, suggesting its potential utility in cancer therapy.

The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation process plays a crucial role in bone formation and homeostasis and is regulated by two intricate processes: cell signal transduction and transcriptional gene expression. Various essential cell signaling pathways, including Wnt, BMP, TGF-β, Hedgehog, PTH, FGF, Ephrin, Notch, Hippo, and Piezo1/2, play a critical role in facilitating osteoblast differentiation, bone formation, and bone homeostasis. Key transcriptional factors in this differentiation process include Runx2, Cbfβ, Runx1, Osterix, ATF4, SATB2, and TAZ/YAP. Furthermore, a diverse array of epigenetic factors also plays critical roles in osteoblast differentiation, bone formation, and homeostasis at the transcriptional level. This review provides an overview of the latest developments and current comprehension concerning the pathways of cell signaling, regulation of hormones, and transcriptional regulation of genes involved in the commitment and differentiation of osteoblast lineage, as well as in bone formation and maintenance of homeostasis. The paper also reviews epigenetic regulation of osteoblast differentiation via mechanisms, such as histone and DNA modifications. Additionally, we summarize the latest developments in osteoblast biology spurred by recent advancements in various modern technologies and bioinformatics. By synthesizing these insights into a comprehensive understanding of osteoblast differentiation, this review provides further clarification of the mechanisms underlying osteoblast lineage commitment, differentiation, and bone formation, and highlights potential new therapeutic applications for the treatment of bone diseases.

Intrinsic and extrinsic factors in the tumour microenvironment (TME) contribute to therapeutic resistance. Here we demonstrate that transforming growth factor (TGF)-β1 produced in the TME increased drug resistance of neuroblastoma (NB) cells.

Human NB cell lines were tested in vitro for their sensitivity to Doxorubicin (DOX) and Etoposide (ETOP) in the presence of tumour-associated macrophages (TAM) and mesenchymal stromal cells/cancer-associated fibroblasts (MSC/CAF). These experiments were validated in xenotransplanted and primary tumour samples.

Drug resistance was associated with an increased expression of efflux transporter and anti-apoptotic proteins. Upregulation was dependent on activation of nuclear factor (NF)-κB by TGF-β-activated kinase (TAK1) and SMAD2. Resistance was reversed upon pharmacologic and genetic inhibitions of NF-κB, and TAK1/SMAD2. Interleukin-6, leukaemia inhibitory factor and oncostatin M were upregulated by this TGF-β/TAK1/NF-κB/SMAD2 signalling pathway contributing to drug resistance via an autocrine loop activating STAT3. An analysis of xenotransplanted NB tumours revealed an increased presence of phospho (p)-NF-κB in tumours co-injected with MSC/CAF and TAM, and these tumours failed to respond to Etoposide but responded if treated with a TGF-βR1/ALK5 inhibitor. Nuclear p-NF-κB was increased in patient-derived tumours rich in TME cells.

The data provides a novel insight into a targetable mechanism of environment-mediated drug resistance.

As a member of the SMAD family, SMAD4 plays a crucial role in several cellular biological processes. However, its function in UVB radiation-induced keratinocyte damage is not yet clarified. Our study aims to provide mechanistic insight for the development of future UVB protective therapies and therapeutics involving SMAD4. HaCaT cells were treated with UVB, and the dose dependence and time dependence of UVB were measured. The cell function of UVB-treated HaCaT cells and the activity of epithelial-mesenchymal transition (EMT) after overexpression or silencing of SMAD4 was observed by flow cytometry, quantitative reverse transcription PCR (qRT-PCR) and Western Blots (WB). We found that a significant decrease in SMAD4 was observed in HaCaT cells induced by UVB. Our data confirm SMAD4 as a direct downstream target of miR-664. The down-regulation of SMAD4 preserved the viability of the UVB-treated HaCaT cells by inhibiting autophagy or apoptosis. Furthermore, the silencing of SMAD4 activated the EMT process in UVB-treated HaCaT cells. Down-regulation of SMAD4 plays a protective role in UVB-treated HaCaT cells via the activation of EMT.

Animal-derived venom, like snake venom, has been proven to be valuable natural resources for the drug development. Previously, snake venom was mainly investigated in its pharmacological activities in regulating coagulation, vasodilation, and cardiovascular function, and several marketed cardiovascular drugs were successfully developed from snake venom. In recent years, snake venom fractions have been demonstrated with anticancer properties of inducing apoptotic and autophagic cell death, restraining proliferation, suppressing angiogenesis, inhibiting cell adhesion and migration, improving immunity, and so on. A number of active anticancer enzymes and peptides have been identified from snake venom toxins, such as L-amino acid oxidases (LAAOs), phospholipase A2 (PLA2), metalloproteinases (MPs), three-finger toxins (3FTxs), serine proteinases (SPs), disintegrins, C-type lectin-like proteins (CTLPs), cell-penetrating peptides, cysteine-rich secretory proteins (CRISPs). In this review, we focus on summarizing these snake venom-derived anticancer components on their anticancer activities and underlying mechanisms. We will also discuss their potential to be developed as anticancer drugs in the future.

The Transforming Growth Factor beta (TGF-β) family consists of numerous secreted peptide growth factors that play significant roles in cell function, tissue patterning, and organismal homeostasis, including wound repair and immunity. Typically studied as homodimers, these ligands have the potential to diversify their functions through ligand interactions that may enhance, repress, or generate novel functions. In the nematode Caenorhabditis elegans, there are only five TGF-β ligands, providing an opportunity to dissect ligand interactions in fewer combinations than in vertebrates. As in vertebrates, these ligands can be divided into bone morphogenetic protein (BMP) and TGF-β/Activin subfamilies that predominantly signal through discrete signaling pathways. The BMP subfamily ligand DBL-1 has been well studied for its role in the innate immune response in C. elegans. Here we show that all five TGF-β ligands play a role in survival on bacterial pathogens. We also demonstrate that multiple TGF-β ligand pairs act nonredundantly as part of this response. We show that the two BMP-like ligands-DBL-1 and TIG-2-function independently of each other in the immune response, while TIG-2/BMP and the TGF-β/Activin-like ligand TIG-3 function together. Structural modeling supports the potential for TIG-2 and TIG-3 to form heterodimers. Additionally, we identify TIG-2 and TIG-3 as members of a rare subset of TGF-β ligands lacking the conserved cysteine responsible for disulfide linking mature dimers. Finally, we show that canonical DBL-1/BMP receptor and Smad signal transducers function in the response to bacterial pathogens, while components of the DAF-7 TGF-β/Activin signaling pathway do not play a major role in survival. These results demonstrate a novel potential for BMP and TGF-β/Activin subfamily ligands to interact and may provide a mechanism for distinguishing the developmental and homeostatic functions of these ligands from an acute response such as the innate immune response to bacterial pathogens.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-β1, the principal form of exosomal TGF-β1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-β signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-β1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-β1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-β1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.

The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs' pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.

Colorectal cancer (CRC) remains a major global health concern, necessitating an in-depth exploration of the intricate molecular mechanisms underlying its progression and potential therapeutic interventions. Transforming Growth Factor-β (TGF-β) signaling, a pivotal pathway implicated in CRC plays a dual role as a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Recent research has shed light on the critical involvement of noncoding RNAs (ncRNAs) in modulating the TGF-β signaling pathway, introducing a new layer of complexity to our understanding of CRC pathogenesis. This comprehensive review synthesizes the current state of knowledge regarding the function and therapeutic potential of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the context of TGF-β signaling in CRC. The intricate interplay between these ncRNAs and key components of the TGF-β pathway is dissected, revealing regulatory networks that contribute to the dynamic balance between tumor suppression and promotion. Emphasis is placed on how dysregulation of specific ncRNAs can disrupt this delicate equilibrium, fostering CRC initiation, progression, and metastasis. Moreover, the review provides a critical appraisal of the emerging therapeutic strategies targeting ncRNAs associated with TGF-β signaling in CRC. The potential of these ncRNAs as diagnostic and prognostic biomarkers is discussed, highlighting their clinical relevance. Additionally, the challenges and prospects of developing RNA-based therapeutics, such as RNA interference and CRISPR/Cas-based approaches, are explored in the context of modulating TGF-β signaling for CRC treatment. In conclusion, this review offers a comprehensive overview of the intricate interplay between ncRNAs and the TGF-β signaling pathway in CRC. By unraveling the functional significance of these regulatory elements, we gain valuable insights into the molecular landscape of CRC, paving the way for the development of novel and targeted therapeutic interventions aimed at modulating the TGF-β signaling cascade through the manipulation of ncRNAs.

Transforming growth factor (TGF)-β1 is a multifunctional cytokine that plays important roles in health and disease. Previous studies have revealed that TGFβ1 activation, signaling, and downstream cell responses including epithelial-mesenchymal transition (EMT) and apoptosis are regulated by the elasticity or stiffness of the extracellular matrix. However, tissues within the body are not purely elastic, rather they are viscoelastic. How matrix viscoelasticity impacts cell fate decisions downstream of TGFβ1 remains unknown. Here, we synthesized polyacrylamide hydrogels that mimic the viscoelastic properties of breast tumor tissue. We found that increasing matrix viscous dissipation reduces TGFβ1-induced cell spreading, F-actin stress fiber formation, and EMT-associated gene expression changes, and promotes TGFβ1-induced apoptosis in mammary epithelial cells. Furthermore, TGFβ1-induced expression of integrin linked kinase (ILK) and colocalization of ILK with vinculin at cell adhesions is attenuated in mammary epithelial cells cultured on viscoelastic substrata in comparison to cells cultured on nearly elastic substrata. Overexpression of ILK promotes TGFβ1-induced EMT and reduces apoptosis in cells cultured on viscoelastic substrata, suggesting that ILK plays an important role in regulating cell fate downstream of TGFβ1 in response to matrix viscoelasticity.

Physiological embryogenesis and adult tissue homeostasis are regulated by transforming growth factor-β (TGF-β), an evolutionarily conserved family of secreted polypeptide factors, acting in an autocrine and paracrine manner. The role of TGF-β in inflammation, fibrosis, and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, especially fibrosis and cancer, overexpressed TGF-β causes extracellular matrix deposition, epithelial-mesenchymal transition, cancer-associated fibroblast formation, and/or angiogenesis. In this review article, we have tried to dive deep into the mechanism of action of TGF-β in inflammation, fibrosis, and carcinogenesis. As TGF-β and its downstream signaling mechanism are implicated in fibrosis and carcinogenesis blocking this signaling mechanism appears to be a promising avenue. However, targeting TGF-β carries substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. There is a need for careful dosing of TGF-β drugs for therapeutic use and patient selection.

Mutations in activin-like kinase 2 (ALK2), e.g., ALK2-R206H, induce aberrant signaling to SMAD1/5/8, leading to Fibrodysplasia Ossificans Progressiva (FOP). In spite of extensive studies, the underlying mechanism is still unclear. Here, we quantified the homomeric and heteromeric interactions of ACVR2A, ACVR2B, ALK2-WT, and ALK2-R206H by combining IgG-mediated immobilization of one receptor with fluorescence recovery after photobleaching (FRAP) measurements on the lateral diffusion of a co-expressed receptor. ACVR2B formed stable homomeric complexes that were enhanced by Activin A (ActA), while ACVR2A required ActA for homodimerization. ALK2-WT, but not ALK2-R206H, exhibited homomeric complexes unaffected by ActA. ACVR2B formed ActA-enhanced heterocomplexes with ALK2-R206H or ALK2-WT, while ACVR2A interacted mainly with ALK2-WT. The extent of the homomeric complex formation of ACVR2A or ACVR2B was reflected in their ability to induce the oligomerization of ALK2-R206H and ALK2-WT. Thus, ACVR2B, which forms dimers without ligand, induced ActA-independent ALK2-R206H clustering but required ActA for enhancing the oligomerization of the largely dimeric ALK2-WT. In contrast, ACVR2A, which undergoes homodimerization in response to ActA, required ActA to induce ALK2-R206H oligomerization. To investigate whether these interactions are translated into signaling, we studied signaling by the FOP-inducing hyperactive ALK2-R206H mutant, with ALK2-WT signaling as control. The activation of SMAD1/5/8 signaling in cells expressing ALK2-R206H alone or together with ACVR2A or ACVR2B was measured by blotting for pSMAD1/5/8 and by transcriptional activation assays using BRE-Luc reporter. In line with the biophysical studies, ACVR2B activated ALK2-R206H without ligand, while activation by ACVR2A was weaker and required ActA. We propose that the homodimerization of ACVR2B or ACVR2A dictates their ability to recruit ALK2-R206H into higher complexes, enabling the homomeric interactions of ALK2-R206H receptors and, subsequently, their activation.

Signaling by TGFβ family cytokines plays a tumor-suppressive role by inducing cell differentiation, while it promotes malignant progression through epithelial-to-mesenchymal transition (EMT). Identification of the mechanisms regulating the switch from tumor suppression to tumor promotion could identify strategies for cancer prevention and treatment. To identify the key genetic alterations that determine the outcome of TGFβ signaling, we used mouse intestinal tumor-derived organoids carrying multiple driver mutations in various combinations to examine the relationship between genotypes and responses to the TGFβ family cytokine activin A. KrasG12D mutation protected organoid cells from activin A-induced growth suppression by inhibiting p21 and p27 expression. Furthermore, Trp53R270H gain-of-function (GOF) mutation together with loss of wild-type Trp53 by loss of heterozygosity (LOH) promoted activin A-induced partial EMT with formation of multiple protrusions on the organoid surface, which was associated with increased metastatic incidence. Histologic analysis confirmed that tumor cells at the protrusions showed loss of apical-basal polarity and glandular structure. RNA sequencing analysis indicated that expression of Hmga2, encoding a cofactor of the SMAD complex that induces EMT transcription factors, was significantly upregulated in organoids with Trp53 GOF/LOH alterations. Importantly, loss of HMGA2 suppressed expression of Twist1 and blocked activin A-induced partial EMT and metastasis in Trp53 GOF/LOH organoids. These results indicate that TP53 GOF/LOH is a key genetic state that primes for TGFβ family-induced partial EMT and malignant progression of colorectal cancer. Activin signaling may be an effective therapeutic target for colorectal cancer harboring TP53 GOF mutations.

KRAS and TP53 mutations shift activin-mediated signaling to overcome growth inhibition and promote partial EMT, identifying a subset of patients with colorectal cancer that could benefit from inhibition of TGFβ signaling.