The Wnt signaling pathway plays a crucial role in development and tissue homeostasis, regulating key cellular processes such as proliferation, differentiation, and apoptosis. However, its abnormal activation is strongly associated with tumorigenesis, metastasis, and resistance to therapy, making it a vital target for cancer treatment. This review provides a comprehensive insight into the role of Wnt signaling in cancer, examining its normal physiological functions, dysregulation in malignancies, and therapeutic potential. We emphasize the importance of predicting Wnt signaling sensitivity and identify key biomarkers across various cancer types. Additionally, we address the challenges and future prospects of Wnt-targeted therapies, including biomarker discovery, advancements in emerging technologies, and their application in clinical practice.

Gene selection is crucial for cancer classification using microarray data. In the interests of improving cancer classification accuracy, in this paper, we developed a new wrapper method called ieGENES for gene selection. First we proposed a parsimonious kernel machine regularization (PKMR) model by using ridge regularization in kernel machine driven classification to tackle multi-collinearity for the sake of stable estimates in high-dimensional settings. Then the ieGENES algorithm was developed to optimally identify relevant genes while iteratively eliminating redundant ones based on leave-one-out cross-validation accuracy. In particular, we developed a new methodology to optimally update model parameters upon gene removal. The ieGENES algorithm was evaluated on six cancer microarray datasets and compared to existing methods. Classification accuracy and number of differentially expressed genes (DEGs) identified were assessed. In terms of gene selection accuracy, the ieGENESoutperformed multiple wrapper methods on 5 out of 6 datasets (Colon, Leukemia, Hepato, Glioma, and Breast Cancers), with statistically significant improvements (p<0.001). For the Colon dataset, ieGENES achieved 96.21% accuracy with 167 DEGs. The proposed ieGENES technique demonstrated superior performance in identifying DEGs for cancer diagnosis comparing with existing techniques. It offers a promising tool for identifying biologically relevant genes in microarray data analysis and biomarker discovery for cancer research.

Colorectal carcinoma is a major health concern globally, with varying prognostic outcomes influenced by molecular markers. E-cadherin and beta-catenin are proteins involved in cellular adhesion and signaling pathways, and their aberrant expression has been implicated in tumor progression and metastasis.

This study aims to evaluate the association between abnormal immunohistochemical expression of E-cadherin and beta-catenin with various clinicopathological parameters in colorectal carcinomas.

A retrospective cross-sectional 3-year analytical study.

A total of 52 colorectal carcinoma tissue samples were analyzed using immunohistochemistry to assess the expression levels of E-cadherin and beta-catenin. Clinicopathological parameters including age, gender, tumor location, tumor differentiation, depth of invasion, perineural invasion, lymphovascular invasion, and nodal involvement were assessed and correlated with protein expression patterns.

SPSS version 24 was used for calculating P values using the Chi-squared test.

Aberrant expression of E-cadherin and beta-catenin was observed in a significant proportion of the tumors. Poorly differentiated tumors showed a marked loss of E-cadherin and abnormal beta-catenin localization. In addition, increased lymphovascular and nodal involvement were significantly associated with these aberrant expression patterns.

The findings suggest that abnormal expression of E-cadherin and beta-catenin is linked to poor tumor differentiation and higher rates of lymphovascular and nodal involvement. These markers may serve as potential biomarkers for assessing prognosis in colorectal carcinoma patients.

Cancer, and the resulting mortality from it, is an ever-increasing concern in global health. Cancer mortality stems from the metastatic progression of the disease, by dissemination of the tumor cells. Epithelial-Mesenchymal Transition, the major hypothesis purported to be the origin of metastasis, confers mesenchymal phenotype to epithelial cells in a variety of contexts, physiological and pathological. EMT in cancer leads to rise of cancer-stem-like cells, drug resistance, relapse, and progression of malignancy. Inhibition of EMT could potentially attenuate the mortality. While novel molecules for inhibiting EMT are underway, repurposing drugs is also being considered as a viable strategy. In this review, Itraconazole is focused upon, as a repurposed molecule to mitigate EMT. Itraconazole is known to inhibit Hedgehog signaling, and light is shed upon the existing evidence, as well as the questions remaining to be answered.

Epithelial-mesenchymal transition (EMT) promotes several cancers by increasing tumor cell motility, disrupting epithelial cell phenotypes, apical-basal polarity, and intracellular connections, and enhancing tumor resistance to immunotherapy and chemotherapy. Mesenchymal-epithelial transition (MET), the opposite of EMT, causes tumor metastasis. EMT drives primary tumor cells, whereas MET inhibits them. Importantly, the complex network of EMT includes cell-cell interactions in the tumor microenvironment. Transcription factors, post-translational regulation, cytokine-mediated signaling, and microRNAs control EMT. In this review, we discussed how molecular mechanisms, signaling networks, and epithelial/mesenchymal states affect cancer treatment resistance and the tumor microenvironment. Research on immunotherapy and chemotherapy problems associated with EMT suggests that targeting EMT might be a potential cancer treatment resistance strategy.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.

Dedifferentiation of osteosarcoma cells leads to poor prognosis. We plan to identify the key molecules that are involved in cell dedifferentiation and explore how they promote the pulmonary metastasis of osteosarcoma cells. We performed a sphere formation assay and confirmed that the spheroid cells could be redifferentiated into osteoblasts, adipocytes, and chondrocytes in specific medium, and the stem cell-like markers Stro-1 and CD117 were detected on the cell surface, which indicated that the spheroid cells were dedifferentiated cells. Thrombospondin 1 (THBS1) and ITGAs were identified as the key molecules in dedifferentiation through mRNA-seq and analysis, and osteosarcoma patients with higher THBS1 expression had a worse prognosis than those with lower THBS1 expression. THBS1 promotes the accumulation of ITGA1 and ITGA6 on the cell membrane in the early phase of dedifferentiation, thereby increasing the phosphorylation of FAK, RasGRF1, and MLC2 in the cytoplasm and promoting cytoskeleton remodeling. Our results suggest that THBS1 promotes cell dedifferentiation and pulmonary metastasis by promoting cytoskeletal remodeling and that ITGA1 and ITGA6 play important roles in mediating extracellular to intracellular signals; this mediating effect takes place mainly in the early phase of dedifferentiation.

The epithelial-to-mesenchymal transition (EMT) is a crucial step in metastasis formation. It enhances the ability of cancer cells' to self-renew and initiate tumors, while also increasing resistance to apoptosis and chemotherapy. Among the signaling pathways a few signaling pathways such as Notch, TGF-beta, and Wnt-beta catenin are critically involved in the epithelial-to-mesenchymal transition (EMT) acquisition. Therefore, regulating EMT is a key strategy for controlling malignant cell behavior. This is done by interconnecting other signaling pathways in many cancer types. Although there is extensive preclinical evidence regarding EMT's function in the development of cancer, there is still a deficiency in clinical translation at the therapeutic level. Thus, there is a need for medications that are both highly effective and with low cytotoxic for modulating EMT transitions at ground level. Thus, this led to the study of the evaluation and efficiency of phytochemicals found in dietary sources of fruits and vegetables and also the combination of small molecular repurposed drugs that can enhance the effectiveness of traditional cancer treatments. This review summarises major EMT-associated pathways and their cross talks with their mechanistic insights and the role of different dietary phytochemicals (curcumin, ginger, fennel, black pepper, and clove) and their natural analogs and also repurposed drugs (metformin, statin, chloroquine, and vitamin D) which are commonly used in regulating EMT in various preclinical studies. This review also investigates the concept of low-toxicity and broad spectrum ("The Halifax Project") approach which can help for site targeting of several key pathways and their mechanism. We also discuss the mechanisms of action, models for our dietary phytochemicals, and repurposed drugs and their combinations used to identify potential anti-EMT activities. Additionally, we also analyzed existing literature and proposed new directions for accelerating the discovery of novel drug candidates that are safe to administer.

BackgroundThe past decade has shown a sharp incline in the human papillomavirus (HPV) infection associated oropharyngeal carcinoma cases, especially in men younger than 60 years old. Tonsils are one of the key sites, within the oropharyngeal region, which shows malignant changes due to HPV infection, and there is very limited literature to understand the specific dynamics in the tonsillar areas.ObjectiveThis critical review was undertaken to explore and unravel the bio-molecular interactions and the role of specific proteins associated with HPV infection induced tumorigenesis for the tonsils.DesignA systematic search of the literature was performed utilising keywords and MeSH terms related to HPV and tonsillar carcinoma in PubMed, Scopus, Embase, and Web of Science without restrictions on dates until July 2023. All studies that reported on molecular biomarkers or genes/genetic proteins in the context of HPV associated tonsillar carcinoma were included in the study.ResultsPreliminary searches revealed a total of 2734 studies of which 23 satisfied the final inclusion criteria and were included. More than 25 proteins and biomarkers were identified, and their role in the malignant process was extracted and compiled. This review also presents a short excerpt on each of the molecules identified to provide a better understanding of the pathogenesis.ConclusionGiven the rapidly increasing number of cases, there is an urgent need for more focused research on virally induced tonsillar cancers, to develop a better understanding, and for clarity of management and treatment.

Metastatic colorectal carcinoma (mCRC) is one of the prevalent subtypes of human cancers and is caused by the alterations of various lifestyle and diet-associated factors. β-catenin, GSK-3β, PI3K-α, AKT1, and NF-κB p50 are known to be the critical regulators of tumorigenesis and immunopathogenesis of mCRC. Unfortunately, current drugs have limited efficacy, side effects and can lead to chemoresistance. Therefore, searching for a nontoxic, efficacious anti-mCRC agent is crucial and of utmost interest. The present study demonstrates the identification of a productive and nontoxic anti-mCRC agent through a five-targets (β-catenin, GSK-3β, PI3K-α, AKT1, and p50)-based and three-tier (binding affinity, pharmacokinetics, and pharmacophore) screening strategy involving a series of 30 phytocompounds having a background of anti-inflammatory/anti-mCRC efficacy alongside 5-fluorouracil (FU), a reference drug. Luteolin (a phyto-flavonoid) was eventually rendered as the most potent and safe phytocompound. This inference was verified through three rounds of validation. Firstly, luteolin was found to be effective against the different mCRC cell lines (HCT-15, HCT-116, DLD-1, and HT-29) without hampering the viability of non-tumorigenic ones (RWPE-1). Secondly, luteolin was found to curtail the clonogenicity of CRC cells, and finally, it also disrupted the formation of colospheroids, a characteristic of metastasis. While studying the mechanistic insights, luteolin was found to inhibit β-catenin activity (a key regulator of mCRC) through direct physical interactions, promoting its degradation by activating GSK3-β and ceasing its activation by inactivating AKT1 and PI3K-α. Luteolin also inhibited p50 activity, which could be useful in mitigating mCRC-associated proinflammatory milieu. In conclusion, our study provides evidence on the efficacy of luteolin against the critical key regulators of immunopathogenesis of mCRC and recommends further studies in animal models to determine the effectiveness efficacy of this natural compound for treating mCRC in the future.

Dysregulated pH is now recognised as a hallmark of cancer. Recent evidence has revealed that the endosomal pH regulator Na+/H+ exchanger NHE9 is upregulated in colorectal cancer to impose a pseudo-starvation state associated with invasion, highlighting an underexplored mechanistic link between adaptive endosomal reprogramming and malignant transformation. In this study, we use a model that quantitatively captures the dynamics of the core regulatory network governing epithelial mesenchymal plasticity. The model recapitulated NHE9-induced calcium signalling and the emergence of migratory phenotypes in colorectal cancer cells. Model predictions were compared with patient data and experimental results from RNA sequencing analysis of colorectal cancer cells with stable NHE9 expression. Mathematical analyses identified that tumours leverage elevated NHE9 levels to delay the transition of cells to a mesenchymal state and allow for metastatic progression. Ectopic expression of NHE9 is sufficient to induce loss of epithelial nature but does not fully couple with gain of mesenchymal state, resulting in a hybrid epithelial-mesenchymal population with increased aggressiveness and metastatic competence. Higher NHE9 expression is associated with cancer cell migration, and the effect appears to be independent of hypoxia status. Our data suggests that alterations in endosomal pH, an evolutionarily conserved starvation response, may be hijacked by colorectal cancer cells to drive phenotypic plasticity and invasion. We propose that cancer cells rewire their endosomal pH not only to meet the demands of rapid cell proliferation, but also to enable invasion, metastasis, and cell survival. Endosomal pH may be an attractive therapeutic target for halting tumour progression.

(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma is often encountered, suggesting PDPN-positive CAFs have emerged. However, PDPN-positive CAFs in early CRC have not been studied well. (Methods) On immunohistochemistry, PDPN expression in the lamina propria or stroma of adenomas, early CRCs, and neuroendocrine tumors, their normal neighbors, and non-neoplastic colorectal lesions were compared. Single-cell RNA sequencing (scRNA-seq) of CRC was used to explore PDPNhigh CAFs' cell origins. (Results) Reticular cells or pericryptal fibroblasts in the lamina propria of adenomas and early CRCs showed higher PDPN expression than did normal mucosae and non-neoplastic lesions (p < 0.01). Pericryptal PDPN expression was a diagnostic feature of adenomas and early CRCs. scRNA-seq of CRCs highlighted that PDPNhigh CAFs had distinctly higher COL4A1, COL4A2, and WNT5A expression, unlike well-known CAFs characterized by high FAP, POSTN, or ACTA2 expression. (Conclusions) We demonstrated that pericryptal fibroblasts and reticular cells in the lamina propria are origins of early-stage CRC CAFs and thus have potential as a diagnostic marker for distinguishing colorectal non-neoplastic from neoplastic lesions.

Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.

Breast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo.

In our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. β-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry.

Both coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in β- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density.

These findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer.

Advancements in nasopharyngeal carcinoma (NPC) treatment have led to a focus on personalized treatment. Circulating tumor cells (CTCs) are important for liquid biopsies and personalized treatment but are not being fully utilized. This study examined how pre- and post-treatment CTC counts, EMT subtypes, clinical characteristics, and patient prognosis are related in order to support the use of liquid biopsy in managing NPC.

This retrospective study included 141 patients with locally advanced NPC. All patients underwent CanPatrol™ CTC detection pre- and post-treatment and were categorized into EMT subtypes: epithelial type, mixed type, and mesenchymal type. This study analyzed CTC enumeration, EMT subtypes, and their associations with clinical characteristics and survival outcomes.

The results indicated a positive correlation between the pre-treatment detection rate of CTCs and N stage (P < 0.01), alongside a positive correlation with the TNM clinical stage (P = 0.02). Additionally, the detection rate of mesenchymal CTCs post-treatment is positively associated with the N stage (P = 0.02). The enumeration of CTCs pre- and post-treatment is negatively correlated with prognosis and has statistical significance. Additionally, an investigation into the EMT subtypes of CTCs revealed a significant association between the presence of mesenchymal CTCs pre- and post-treatment and decreased overall survival (OS) (P < 0.05). Furthermore, T stage, N stage, TNM clinical stage, and Epstein-Barr virus (EBV) DNA were also significantly correlated with OS.

The study found that mesenchymal CTCs pre- and post-treatment, as well as the number of CTCs, were linked to a poor prognosis.

The WNT/β-catenin signaling pathway plays crucial roles in tumorigenesis and relapse, metastasis, drug resistance, and tumor stemness maintenance. In most tumors, the WNT/β-catenin signaling pathway is often aberrantly activated. The therapeutic usefulness of inhibition of WNT/β-catenin signaling has been reported to improve the efficiency of different cancer treatments and this inhibition of signaling has been carried out using different methods including pharmacological agents, short interfering RNA (siRNA), and antibodies. Here, we review the WNT-inhibitory effects of some FDA-approved drugs and natural products in cancer treatment and focus on recent progress of the WNT signaling inhibitors in improving the efficiency of chemotherapy, immunotherapy, gene therapy, and physical therapy. We also classified these FDA-approved drugs and natural products according to their structure and physicochemical properties, and introduced briefly their potential mechanisms of inhibiting the WNT signaling pathway. The review provides a comprehensive understanding of inhibitors of WNT/β-catenin pathway in various cancer therapeutics. This will benefit novel WNT inhibitor development and optimal clinical use of WNT signaling-related drugs in synergistic cancer therapy.

Intrahepatic cholangiocarcinoma (iCCA) is recognized worldwide as the second leading cause of morbidity and mortality among primary liver cancers, showing a continuously increasing incidence rate in recent years. iCCA aggressiveness is revealed through its rapid and silent intrahepatic expansion and spread through the lymphatic system leading to late diagnosis and poor prognoses. Multi-omics studies have aggregated information derived from single-omics data, providing a more comprehensive understanding of the phenomena being studied. These approaches are gradually becoming powerful tools for investigating the intricate pathobiology of iCCA, facilitating the correlation between molecular signature and phenotypic manifestation. Consequently, preliminary stratifications of iCCA patients have been proposed according to their "omics" features opening the possibility of identifying potential biomarkers for early diagnosis and developing new therapies based on personalized medicine (PM). The focus of this review is to provide new and advanced insight into the molecular pathobiology of the iCCA, starting from single- to the latest multi-omics approaches, paving the way for translating new basic research into therapeutic practices.

Approximately 20% of patients with colorectal cancer (CRC) are diagnosed with a mucinous subtype of this tumor, have a worse prognosis, and often show resistance to available therapies. Molecules from the mucin family are involved in the regulation of epithelial-mesenchymal transition (EMT), which significantly determines the cancer aggressiveness. This study aimed to examine the diagnostic and prognostic significance of mucinous histology and EMT markers in patients with early-onset CRC and their association with disease severity and tumor characteristics. This study included tumor tissue samples from 106 patients diagnosed with CRC before the age of 45, 53 with mucinous and 53 with non-mucinous tumors. The EMT status was determined by immunohistochemical analysis of E-cadherin and Vimentin in tissue sections. Mucinous tumors had significantly higher Mucin-1 (p < 0.001) and cytoplasmic E-cadherin (p = 0.043) scores; they were significantly less differentiated (p = 0.007), more advanced (p = 0.027), and predominately affected right the colon (p = 0.039) compared to non-mucinous tumors. Epithelial tumors were significantly better differentiated (p = 0.034) and with less prominent tumor budding (p < 0.001) than mesenchymal tumors. Mucin-1 and Vimentin were independent predictors of tumor differentiation (p = 0.006) and budding (p = 0.001), respectively. Mucinous histology and EMT markers are significant predictors of disease severity and tumor characteristics in early-onset colorectal cancer.

Collective cell invasion (CCI), a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. In earlier efforts on homogenous cancer cell populations, this framework revealed the relative ranges of interactions, including cell-cell and cell-ECM adhesion that drove collective, dispersed, and mixed multimodal invasion. Here, we constitute a tumor core of two separate cell subsets showing distinct intra- and inter-subset cell-cell or cell-ECM adhesion strengths. These two subsets of cells are arranged to varying extents of spatial intermingling, which we call the heterogeneity index (HI). We observe that low and high inter-subset cell adhesion favors invasion of high-HI and low-HI intermingled populations with distinct intra-subset cell-cell adhesion strengths, respectively. In addition, for explored values of cell-ECM adhesion strengths, populations with high HI values collectively invade better than those with lower HI values. We then asked how spatial invasion is regulated by progressively intermingled cellular subsets that are epithelial, i.e., showed high cell-cell but poor cell-ECM adhesion, and mesenchymal, i.e., with reversed adhesion strengths to the former. Here too, inter-subset adhesion plays an important role in contextualizing the proportionate relationship between HI and invasion. An exception to this relationship is seen for cases of heterogeneous cell-ECM adhesion where sub-maximal HI patterns with higher outer localization of cells with stronger ECM adhesion collectively invade better than their relatively higher-HI counterparts. Our simulations also reveal how adhesion heterogeneity qualifies collective invasion, when either cell-cell or cell-ECM adhesion type is varied but results in an invasive dispersion when both adhesion types are simultaneously altered.

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically 'hot' TB remain poorly understood.

We quantified the number of TB by haematoxylin-eosin (H&E) sections and the densities of CD3+ and CD8+ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed.

In a CRC cohort of 351 cases, low-grade TB was associated with high CD3+ and CD8+ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3+ and CD8+ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration.

KRT17 can be employed as a new indicator for distinguishing different immunological TBs.

Nowadays, hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths, and identifying the effective factors in causing this disease can play an important role in its prevention and treatment. Tumors provide effective agents for invasion and metastasis to other organs by establishing appropriate communication between cancer cells and the microenvironment. Epithelial-to-mesenchymal transition (EMT) can be mentioned as one of the effective phenomena in tumor invasion and metastasis. Several factors are involved in inducing this phenomenon in the tumor microenvironment, which helps the tumor survive and migrate to other places. It can be effective to identify these factors in the use of appropriate treatment strategies and greater patient survival. This study investigated the molecular differences between tumor border cells and tumor core cells or internal tumor cells in HCC for specific EMT genes. Expression of NOTCH1, ID1, and LST1 genes showed a significant increase at the HCC tumor border. Targeting these genes can be considered as a useful therapeutic strategy to prevent distant metastasis in HCC patients.

Epithelial-to-mesenchymal transition (EMT), a biological phenomenon of cellular plasticity initially reported in embryonic development, has been increasingly recognized for its importance in cancer progression and metastasis. Despite tremendous progress being made in the past 2 decades in our understanding of the molecular mechanism and functional importance of EMT in cancer, there are several mysteries around EMT that remain unresolved. In this Unsolved Mystery, we focus on the variety of EMT types in metastasis, cooperative and collective EMT behaviors, spatiotemporal characterization of EMT, and strategies of therapeutically targeting EMT. We also highlight new technical advances that will facilitate the efforts to elucidate the unsolved mysteries of EMT in metastasis.

To overcome the limitations of in vitro two-dimensional (2D) cancer models in mimicking the complexities of the native tumor milieu, three-dimensional (3D) engineered cancer models using biomimetic materials have been introduced to more closely recapitulate the key attributes of the tumor microenvironment. Specifically, for colorectal cancer (CRC), a few studies have developed 3D engineered tumor models to investigate cell-cell interactions or efficacy of anti-cancer drugs. However, recapitulation of CRC cell line phenotypic differences within a 3D engineered matrix has not been systematically investigated. Here, we developed an in vitro 3D engineered CRC (3D-eCRC) tissue model using the natural-synthetic hybrid biomaterial PEG-fibrinogen and three CRC cell lines, HCT 116, HT-29, and SW480. To better recapitulate native tumor conditions, our 3D-eCRC model supported higher cell density encapsulation (20 × 106  cells/mL) and enabled longer term maintenance (29 days) as compared to previously reported in vitro CRC models. The 3D-eCRCs formed using each cell line demonstrated line-dependent differences in cellular and tissue properties, including cellular growth and morphology, cell subpopulations, cell size, cell granularity, migration patterns, tissue growth, gene expression, and tissue stiffness. Importantly, these differences were found to be most prominent from Day 22 to Day 29, thereby indicating the importance of long-term culture of engineered CRC tissues for recapitulation and investigation of mechanistic differences and drug response. Our 3D-eCRC tissue model showed high potential for supporting future in vitro comparative studies of disease progression, metastatic mechanisms, and anti-cancer drug candidate response in a CRC cell line-dependent manner.

The resistance of cancer cells to chemotherapy, also known as chemo-resistance, poses a significant obstacle to cancer treatment and can ultimately result in patient mortality. Epithelial-mesenchymal transition (EMT) is one of the many factors and processes responsible for chemo-resistance. Studies have shown that targeting EMT can help overcome chemo-resistance, and nanotechnology and nanomedicine have emerged as promising approaches to achieve this goal. This article discusses the potential of nanotechnology in inhibiting EMT and proposes a viable strategy to combat chemo-resistance in various solid tumors, including breast cancer, lung cancer, pancreatic cancer, glioblastoma, ovarian cancer, gastric cancer, and hepatocellular carcinoma. While nanotechnology has shown promising results in targeting EMT, further research is necessary to explore its full potential in overcoming chemo-resistance and discovering more effective methods in the future.

TWIST1 is a transcription factor that is necessary for healthy neural crest migration, mesoderm development, and gastrulation. It functions as a key regulator of epithelial-to-mesenchymal transition (EMT), a process by which cells lose their polarity and gain the ability to migrate. EMT is often reactivated in cancers, where it is strongly associated with tumor cell invasion and metastasis. Early work on TWIST1 in adult tissues focused on its transcriptional targets and how EMT gave rise to metastatic cells. In recent years, the roles of TWIST1 and other EMT factors in cancer have expanded greatly as our understanding of tumor progression has advanced. TWIST1 and related factors are frequently tied to cancer cell stemness and changes in therapeutic responses and thus are now being viewed as attractive therapeutic targets. In this review, we highlight non-metastatic roles for TWIST1 and related EMT factors in cancer and other disorders, discuss recent findings in the areas of therapeutic resistance and stemness in cancer, and comment on the potential to target EMT for therapy. Further research into EMT will inform novel treatment combinations and strategies for advanced cancers and other diseases.

TGFβ signaling and the DNA damage response (DDR) are two cellular toolboxes with a strong impact on cancer biology. While TGFβ as a pleiotropic cytokine affects essentially all hallmarks of cancer, the multifunctional DDR mostly orchestrates cell cycle progression, DNA repair, chromatin remodeling and cell death. One oncogenic effect of TGFβ is the partial activation of epithelial-to-mesenchymal transition (EMT), conferring invasiveness, cellular plasticity and resistance to various noxae. Several reports show that both individual networks as well as their interface affect chemo-/radiotherapies. However, the underlying mechanisms remain poorly resolved. EMT often correlates with TGFβ-induced slowing of proliferation, yet numerous studies demonstrate that particularly the co-activated EMT transcription factors counteract anti-proliferative signaling in a partially non-redundant manner. Collectively, evidence piled up over decades underscore a multifaceted, reciprocal inter-connection of TGFβ signaling / EMT with the DDR / cell cycle progression, which we will discuss here. Altogether, we conclude that full cell cycle arrest is barely compatible with the propagation of oncogenic EMT traits and further propose that 'EMT-linked DDR plasticity' is a crucial, yet intricate facet of malignancy, decisively affecting metastasis formation and therapy resistance.

LncRNAs are a class of non-coding RNAs that play an important role in regulating gene expression. However, their specific molecular mechanisms in gastric carcinogenesis and metastasis need further exploration. TCGA data showed that the expression of MFGE8, which was closely related to survival, was significantly positively correlated with lncRNA SNHG14. And moreover, the results of high-throughput sequencing and qRT-PCR showed that lncRNA SNHG14 was significantly elevated in gastric cancer. Further, in vitro functional realization showed that lncRNA SNHG14 overexpression significantly increased gastric cancer's proliferation, invasion and migration. Animal experiments also showed that lncRNA SNHG14 overexpression promoted tumorigenesis and metastasis in vivo. Mechanistically, MFGE8 activates the expression of lncRNA SNHG14, which activates the cellular EMT by stabilizing CDH2. Our study suggests that lncRNA SNHG14 could be a potential target for gastric cancer therapy.

Phenotypic plasticity was recently incorporated as a hallmark of cancer. This plasticity can manifest along many interconnected axes, such as stemness and differentiation, drug-sensitive and drug-resistant states, and between epithelial and mesenchymal cell-states. Despite growing acceptance for phenotypic plasticity as a hallmark of cancer, the dynamics of this process remains poorly understood. In particular, the knowledge necessary for a predictive understanding of how individual cancer cells and populations of cells dynamically switch their phenotypes in response to the intensity and/or duration of their current and past environmental stimuli remains far from complete. Here, we present recent investigations of phenotypic plasticity from a systems-level perspective using two exemplars: epithelial-mesenchymal plasticity in carcinomas and phenotypic switching in melanoma. We highlight how an integrated computational-experimental approach has helped unravel insights into specific dynamical hallmarks of phenotypic plasticity in different cancers to address the following questions: a) how many distinct cell-states or phenotypes exist?; b) how reversible are transitions among these cell-states, and what factors control the extent of reversibility?; and c) how might cell-cell communication be able to alter rates of cell-state switching and enable diverse patterns of phenotypic heterogeneity? Understanding these dynamic features of phenotypic plasticity may be a key component in shifting the paradigm of cancer treatment from reactionary to a more predictive, proactive approach.

Ovarian cancer is the leading cause of death from gynecological malignancies, with serous carcinoma being the most common histopathologic subtype. Epithelial-mesenchymal transition (EMT) correlates with increased metastatic potential, whereas the transcription factor SRY-box transcription factor 11 (SOX11) is overexpressed in diverse malignancies.

In the present study, we aimed to evaluate the potential role of the immunohistochemical expression of SOX11 in 30 serous ovarian carcinomas in association with E-cadherin and vimentin expression as well as with patients' clinicopathological data.

Most of the examined cases showed concurrent expression of E-cadherin and vimentin, whereas SOX11 was expressed in a minority of the cases (26.7%). Interestingly, the positive cases more frequently had a metastatic disease at the time of diagnosis compared with the negative cases (p = 0.09), an association, however, of marginal significance. Moreover, there was a negative correlation between E-cadherin and SOX11 expression (p = 0.0077) and a positive correlation between vimentin and SOX11 expression (p = 0.0130).

The present work, for the first time, provides preliminary evidence of a possible implication of SOX11 overexpression in the promotion of EMT in metastatic serous ovarian cancer, thereby endorsing tumor metastasis.

Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR-100-5p is known to be changed in DM patients and can suppress the expression of E-cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E-cadherin and nuclear β-catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin-fixed paraffin-embedded tissue sections. TaqMan miR assays were applied to assess miR-100-5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation-specific polymerase chain reaction. Immunohistochemistry revealed that decreased E-cadherin expression and increased nuclear β-catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long-duration DM (≥3 years)  was a significant factor contributing to CDH1 promoter methylation (p < 0.01), while miR-100-5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR-100-5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR-100-5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease-free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis.

Limb-Bud and Heart (LBH) is a developmental transcription co-factor deregulated in cancer, with reported oncogenic and tumor suppressive effects. However, LBH expression in most cancer types remains unknown, impeding understanding of its mechanistic function Here, we performed systematic bioinformatic and TMA analysis for LBH in >20 different cancer types. LBH was overexpressed in most cancers compared to normal tissues (>1.5-fold; p < 0.05), including colon-rectal, pancreatic, esophageal, liver, stomach, bladder, kidney, prostate, testicular, brain, head & neck cancers, and sarcoma, correlating with poor prognosis. The cancer types showing LBH downregulation were lung, melanoma, ovarian, cervical, and uterine cancer, while both LBH over- and under-expression were observed in hematopoietic malignancies. In cancers with LBH overexpression, the LBH locus was frequently hypomethylated, identifying DNA hypomethylation as a potential mechanism for LBH dysregulation. Pathway analysis identified a universal, prognostically significant correlation between LBH overexpression and the WNT-Integrin signaling pathways. Validation of the clinical association of LBH with WNT activation in gastrointestinal cancer cell lines, and in colorectal patient samples by IHC uncovered that LBH is specifically expressed in tumor cells with nuclear beta-catenin at the invasive front. Collectively, these data reveal a high degree of LBH dysregulation in cancer and establish LBH as pan-cancer biomarker for detecting WNT hyperactivation in clinical specimens.

In the colorectal cancer (CRC) tumor microenvironment, cancerous and precancerous cells continuously experience mechanical forces associated with peristalsis. Given that mechanical forces like shear stress and strain can positively impact cancer progression, we explored the hypothesis that peristalsis may also contribute to malignant progression in CRC. We defined malignant progression as enrichment of cancer stem cells and the acquisition of invasive behaviors, both vital to CRC progression.

We leveraged our peristalsis bioreactor to expose CRC cell lines (HCT116), patient-derived xenograft (PDX1,2) lines, or non-cancerous intestinal cells (HIEC-6) to forces associated with peristalsis in vitro. Cells were maintained in static control conditions or exposed to peristalsis for 24 h prior to assessment of cancer stem cell (CSC) emergence or the acquisition of invasive phenotypes.

Exposure of HCT116 cells to peristalsis significantly increased the emergence of LGR5+ CSCs by 1.8-fold compared to static controls. Peristalsis enriched LGR5 positivity in several CRC cell lines, notably significant in KRAS mutant lines. In contrast, peristalsis failed to increase LGR5+ in non-cancerous intestinal cells, HIEC-6. LGR5+ emergence downstream of peristalsis was dependent on ROCK and Wnt activity, and not YAP1 activation. Additionally, HCT116 cells adopted invasive morphologies when exposed to peristalsis, with increased filopodia density and epithelial to mesenchymal gene expression, in a Wnt dependent manner.

Peristalsis associated forces drive malignant progression of CRC via ROCK, YAP1, and Wnt-related mechanotransduction.

The online version contains supplementary material available at 10.1007/s12195-023-00776-w.

Colorectal cancer (CRC) is the third most widespread cancer and the fourth leading lethal disease among different societies. It is thought that CRC accounts for about 10% of all newly diagnosed cancer cases with high-rate mortality. lncRNAs, belonging to non-coding RNAs, are involved in varied cell bioactivities. Emerging data have confirmed a significant alteration in lncRNA transcription under anaplastic conditions. This systematic review aimed to assess the possible influence of abnormal mTOR-associated lncRNAs in the tumorigenesis of colorectal tissue. In this study, the PRISMA guideline was utilized based on the systematic investigation of published articles from seven databases. Of the 200 entries, 24 articles met inclusion criteria and were used for subsequent analyses. Of note, 23 lncRNAs were prioritized in association with the mTOR signaling pathway with up-regulation (79.16%) and down-regulation (20.84%) trends. Based on the obtained data, mTOR can be stimulated or inhibited during CRC by the alteration of several lncRNAs. Determining the dynamic activity of mTOR and relevant signaling pathways via lncRNAs can help us progress novel molecular therapeutics and medications.

Tumor cells invade and spread through a procedure termed as epithelial-to-mesenchymal cell transition (EMT). EMT is triggered by any alterations in the genes that encode the extracellular matrix (ECM) proteins, the enzymes that break down the ECM, and the activation of the genes that causes the epithelial cell to change into a mesenchymal type. The transcription factors NF-κB, Smads, STAT3, Snail, Zeb, and Twist are activated by inflammatory cytokines, for instance, Tumor Necrosis Factor, Tumor Growth Factors, Interleukin-1, Interleukin-8, and Interleukin-6, which promotes EMT.

The current piece of work has been reviewed from the literature works published in last 10 years on the role interleukins in inflammation-mediated tumor immune microenvironment modulation in colorectal cancer pathogenesis utilizing the databases like Google Scholar, PubMed, Science Direct.

Recent studies have demonstrated that pathological situations, such as epithelial malignancies, exhibit EMT characteristics, such as the downregulation of epithelial markers and the overexpression of mesenchymal markers. Several growing evidence have also proved its existence in the human colon during the carcinogenesis of colorectal cancer. Most often, persistent inflammation is thought to be one factor contributing to the initiation of human cancers, such as colorectal cancer (CRC). Therefore, according to epidemiologic and clinical research, people with ulcerative colitis and Crohn's disease have a greater probability of developing CRC.

A substantial amount of data points to the involvement of the NF-κB system, SMAD/STAT3 signaling cascade, microRNAs, and the Ras-mitogen-activated protein kinase/Snail/Slug in the epithelial-to-mesenchymal transition-mediated development of colorectal malignancies. As a result, EMT is reported to play an active task in the pathogenesis of colorectal cancer, and therapeutic interventions targeting the inflammation-mediated EMT might serve as a novel strategy for treating CRC. The illustration depicts the relationship between interleukins and their receptors as a driver of CRC development and the potential therapeutic targets.

Epithelial-mesenchymal plasticity (EMP) is a key driver of cancer metastasis and therapeutic resistance, through which cancer cells can reversibly and dynamically alter their molecular and functional traits along the epithelial-mesenchymal spectrum. While cells in the epithelial phenotype are usually tightly adherent, less metastatic, and drug-sensitive, those in the hybrid epithelial/mesenchymal and/or mesenchymal state are more invasive, migratory, drug-resistant, and immune-evasive. Single-cell studies have emerged as a powerful tool in gaining new insights into the dynamics of EMP across various cancer types. Here, we review many recent studies that employ single-cell analysis techniques to better understand the dynamics of EMP in cancer both in vitro and in vivo. These single-cell studies have underlined the plurality of trajectories cells can traverse during EMP and the consequent heterogeneity of hybrid epithelial/mesenchymal phenotypes seen at both preclinical and clinical levels. They also demonstrate how diverse EMP trajectories may exhibit hysteretic behavior and how the rate of such cell-state transitions depends on the genetic/epigenetic background of recipient cells, as well as the dose and/or duration of EMP-inducing growth factors. Finally, we discuss the relationship between EMP and patient survival across many cancer types. We also present a next set of questions related to EMP that could benefit much from single-cell observations and pave the way to better tackle phenotypic switching and heterogeneity in clinic.

The interaction between neoplastic and stromal cells within a tumor mass plays an important role in cancer biology. However, it is challenging to distinguish between tumor and stromal cells in mesenchymal tumors because lineage-specific cell surface markers typically used in other cancers do not distinguish between the different cell subpopulations. Desmoid tumors consist of mesenchymal fibroblast-like cells driven by mutations stabilizing beta-catenin. Here we aimed to identify surface markers that can distinguish mutant cells from stromal cells to study tumor-stroma interactions. We analyzed colonies derived from single cells from human desmoid tumors using a high-throughput surface antigen screen, to characterize the mutant and nonmutant cells. We found that CD142 is highly expressed by the mutant cell populations and correlates with beta-catenin activity. CD142-based cell sorting isolated the mutant population from heterogeneous samples, including one where no mutation was previously detected by traditional Sanger sequencing. We then studied the secretome of mutant and nonmutant fibroblastic cells. PTX3 is one stroma-derived secreted factor that increases mutant cell proliferation via STAT6 activation. These data demonstrate a sensitive method to quantify and distinguish neoplastic from stromal cells in mesenchymal tumors. It identifies proteins secreted by nonmutant cells that regulate mutant cell proliferation that could be therapeutically.

Distinguishing between neoplastic (tumor) and non-neoplastic (stromal) cells within mesenchymal tumors is particularly challenging, because lineage-specific cell surface markers typically used in other cancers do not differentiate between the different cell subpopulations. Here, we developed a strategy combining clonal expansion with surface proteome profiling to identify markers for quantifying and isolating mutant and nonmutant cell subpopulations in desmoid tumors, and to study their interactions via soluble factors.

Although venous invasion (VI) is common in colorectal cancers (CRCs) and is associated with distant metastasis, the 3-dimensional (3D) microscopic features and associated mechanisms of VI are not well elucidated. To characterize the patterns of VI, 103 tissue slabs were harvested from surgically resected CRCs with ≥pT2. They were cleared using the modified immunolabeling-enabled 3D imaging of solvent-cleared organs method, labeled with multicolor fluorescent antibodies, including antibodies against cytokeratin 19, desmin, CD31, and E-cadherin, and visualized by confocal laser scanning microscopy. VI was classified as intravasation, intraluminal growth, and/or extravasation, and 2-dimensional and 3D microscopic features were compared. VI was detected more frequently in 3D (56/103 [54.4%]) than in conventional 2-dimensional hematoxylin and eosin-stained slides (33/103 [32%]; P < .001). When VI was present, it was most commonly in the form of intraluminal growth (51/56), followed by extravasation (13/56) and intravasation (5/56). The mean length of intraluminal growth was 334.0 ± 212.4 μm. Neoplastic cell projections extended from cancer cell clusters in the connective tissue surrounding veins, penetrated the smooth muscle layer, and then grew into and filled the venous lumen. E-cadherin expression changed at each invasion phase; intact E-cadherin expression was observed in the cancer cells in the venous walls, but its expression was lost in small clusters of intraluminal neoplastic cells. In addition, reexpression of E-cadherin was observed when cancer cells formed well-oriented tubular structures and accumulated and grew along the luminal side of the venous wall. In contrast, singly scattered cancer cells and cancer cells with poorly defined tubular structures showed loss of E-cadherin expression. E-cadherin expression was intact in the large cohesive clusters of extravasated cancer cells. However, singly scattered cells and smaller projections of neoplastic cells in the stroma outward of venous wall showed a loss of E-cadherin expression. In conclusion, VI was observed in more than half of the CRCs analyzed by 3D histopathologic image reconstruction. Once inside a vein, neoplastic cells can grow intraluminally. The epithelial-mesenchymal transition is not maintained during VI of CRCs.

Wheat (Triticum aestivum L., 2n = 6x = 42, AABBDD) is the world's most widely cultivated crop and an important staple food for humans, accounting for one-fifth of calories consumed. Proteins encoded by the regulator of chromosome condensation 1 (RCC1) are highly conserved among eukaryotes and consist of seven repeated domains that fold into a seven-bladed propeller structure. In this study, a total of 76 RCC1 genes of bread wheat were identified via a genome-wide search, and their phylogenetic relationship, gene structure, protein-conserved domain, chromosome localization, conserved motif, and transcription factor binding sites were systematically analyzed using the bioinformatics approach to indicate the evolutionary and functional features of these genes. The expression patterns of 76 TaRCC1 family genes in wheat under various stresses were further analyzed, and RT-PCR verified that RCC1-3A (TraesCS3A02G362800), RCC1-3B (TraesCS3B02G395200), and RCC1-3D (TraesCS3D02G35650) were significantly induced by salt, cold, and drought stresses. Additionally, the co-expression network analysis and binding site prediction suggested that Myb-7B (TraesCS7B02G188000) and Myb-7D (TraesCS7D02G295400) may bind to the promoter of RCC1-3A/3B and upregulate their expression in response to abiotic stresses in wheat. The results have furthered our understanding of the wheat RCC1 family members and will provide important information for subsequent studies and the use of RCC1 genes in wheat.

Intratumoral heterogeneity associates with more aggressive disease progression and worse patient outcomes. Understanding the reasons enabling the emergence of such heterogeneity remains incomplete, which restricts our ability to manage it from a therapeutic perspective. Technological advancements such as high-throughput molecular imaging, single-cell omics, and spatial transcriptomics allow recording of patterns of spatiotemporal heterogeneity in a longitudinal manner, thus offering insights into the multiscale dynamics of its evolution. Here, we review the latest technological trends and biological insights from molecular diagnostics as well as spatial transcriptomics, both of which have witnessed burgeoning growth in the recent past in terms of mapping heterogeneity within tumor cell types as well as the stromal constitution. We also discuss ongoing challenges, indicating possible ways to integrate insights across these methods to have a systems-level spatiotemporal map of heterogeneity in each tumor and a more systematic investigation of the implications of heterogeneity for patient outcomes.