Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo.

Three-dimensional organoid culture technologies have revolutionized cancer research by allowing for more realistic and scalable reproductions of both tumour and microenvironmental structures1-3. This has enabled better modelling of low-complexity cancer cell behaviours that occur over relatively short periods of time4. However, available organoid systems do not capture the intricate evolutionary process of cancer development in terms of tissue architecture, cell diversity, homeostasis and lifespan. As a consequence, oncogenesis and tumour formation studies are not possible in vitro and instead require the extensive use of animal models, which provide limited spatiotemporal resolution of cellular dynamics and come at a considerable cost in terms of resources and animal lives. Here we developed topobiologically complex mini-colons that are able to undergo tumorigenesis ex vivo by integrating microfabrication, optogenetic and tissue engineering approaches. With this system, tumorigenic transformation can be spatiotemporally controlled by directing oncogenic activation through blue-light exposure, and emergent colon tumours can be tracked in real-time at the single-cell resolution for several weeks without breaking the culture. These induced mini-colons display rich intratumoural and intertumoural diversity and recapitulate key pathophysiological hallmarks displayed by colorectal tumours in vivo. By fine-tuning cell-intrinsic and cell-extrinsic parameters, mini-colons can be used to identify tumorigenic determinants and pharmacological opportunities. As a whole, our study paves the way for cancer initiation research outside living organisms.

Genomic and Pathologic Profiling of Very Well-Differentiated Gastric Adenocarcinoma of Intestinal Type: A Study With Emphasis on Diffuse-Type Transformation.

Very well-differentiated adenocarcinoma of intestinal type is a distinct subtype of gastric cancer characterized by anastomosing glands with a hand-in-hand pattern and low-grade cytologic atypia resembling intestinal metaplasia. This is a slow-growing neoplasm with an indolent clinical course; however, a subset demonstrates transformation into adenocarcinoma with higher-grade histology, typically diffuse-type carcinoma, and behaves aggressively. This study aimed to better characterize the genomic and pathologic features, with a focus on factors associated with diffuse-type transformation. A total of 58 cases with (n=31) and without (n=27) diffuse-type transformation were analyzed for molecular and pathologic features. First, comprehensive deep DNA sequencing was conducted in 18 cases (discovery cohort), followed by a digital droplet polymerase chain reaction of hot spot RHOA mutations in 40 cases (validation cohort). In total, RHOA mutations were the most common alteration (34%), followed by loss of ARID1A (12%), p53 alterations (10%), and CLDN18 :: ARHGAP26/6 fusions (3.4%). FGFR2 amplification was identified in an advanced case with a p53 alteration. Altered p53 expression was recognized only in higher-grade components and was significantly associated with advanced disease ( P =0.0015) and diffuse-type transformation ( P =0.026). A mixed mucin phenotype was also strongly correlated with advanced disease ( P <0.001) and diffuse-type transformation ( P <0.001). Decreased E-cadherin expression was frequently observed (74%) in poorly cohesive components. This study demonstrated that a subset of RHOA -mutant diffuse-type gastric cancers develops through the transformation of very well-differentiated adenocarcinoma of intestinal type. Our observations suggest a mixed mucin phenotype as a risk factor and alterations in p53 and E-cadherin as drivers of diffuse-type transformation.

Inactivation of the Tumor Suppressor CYLD Sensitizes Mice to Breast Cancer Development.

BACKGROUND/AIM: Breast cancer is a leading cause of cancer-related deaths among women. Down-regulation of the tumor suppressor gene Cyld in breast cancer has been linked to a poor prognosis. This study investigated the role of Cyld in breast cancer using conditional mutant mouse models carrying a Cyld mutation, which inactivates the deubiquitinating activity of its protein product CYLD in mammary epithelial cells. MATERIALS AND METHODS: We examined the potential of CYLD inactivation to induce mammary tumors spontaneously or modify the susceptibility of mice to mammary tumorigenesis by DMBA treatment or ErbB2 over-expression. RESULTS: CYLD inactivation significantly increased susceptibility to breast cancer induced by either DMBA treatment or ErbB2 over-expression. Moreover, while CYLD inactivation alone did not lead to spontaneous mammary tumorigenesis, it did contribute to the formation of multifocal hyperplastic lesions in virgin mice of predominantly FVB/NJ background. CONCLUSION: Our study demonstrates the tumor enhancing potential of CYLD inactivation in mammary tumorigenesis in vivo and establishes novel relevant mouse models that can be exploited for developing prognostic and therapeutic protocols.

Evaluation of stromal myofibroblasts in oral submucous fibrosis and its malignant transformation: An immunohistochemical study.

BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous lesion, with oral squamous cell carcinoma (OSCC) being the most prevalent malignancy affecting the oral mucosa. The malignant transformation of OSF into OSCC is estimated to occur in 7-13% of cases. Myofibroblasts (MFs) play pivotal roles in both physiological and pathological processes, such as wound healing and tumorigenesis, respectively. This study aimed to explore the involvement of MFs in the progression of OSF and its malignant transformation. MATERIALS AND METHODS: In total, 94 formalin-fixed paraffin-embedded tissue blocks were collected, including normal oral mucosa (NOM; n = 10), early-moderate OSF (EMOSF; n = 29), advanced OSF (AOSF; n = 29), paracancerous OSF (POSF; n = 21), and OSCC (n = 5) samples. Alpha-smooth muscle actin was used for the immunohistochemical identification of MFs. RESULTS: NOM exhibited infrequent expression of MFs. A higher staining index of MFs was found in AOSF, followed by EMOSF and NOM. Additionally, a significant increase in the staining index of MFs was found from EMOSF to POSF and OSCC. The staining index of MFs in NOM, EMOSF, AOSF, POSF, and OSCC was 0.14 ± 0.2, 1.69 ± 1.4, 2.47 ± 1.2, 3.57 ± 2.6, and 8.86 ± 1.4, respectively. All results were statistically significant (P < 0.05). CONCLUSIONS: The expression of MFs exhibited a gradual increase as the disease progressed from mild to malignant transformation, indicating the contributory role of MFs in the fibrogenesis and potential tumorigenesis associated with OSF.

Squamous Cell Carcinoma Arising From Epidermal Cyst: A Case Series of 9 Patients With a Literature Review.

ABSTRACT: Epidermal cysts are among the most common benign subcutaneous tumors. However, malignant transformation of benign epidermal cysts into squamous carcinomas has been reported. Owing to its low incidence rate, the clinical and pathological features of this condition are not well understood. This study aimed to analyze the clinical and pathological characteristics of the malignant transformation of epidermal cysts, which could suggest an appropriate treatment strategy. We conducted a retrospective study of 9 patients diagnosed with squamous cell carcinoma arising from epidermal cysts. All patients underwent surgical excision, and clinical information regarding patient demographics, tumor characteristics, treatment, and outcomes was analyzed. The average age at diagnosis was 57.3 years, with an average latency period of 15.4 years. Five patients had undergone prior cyst excision or drainage, with an average of 2.3 episodes of recurrence. Surgical excision was the primary treatment in all cases, and 2 patients with margin involvement at the final pathology underwent re-excision with additional resection margins. No recurrence was observed during the follow-up period. Four patients had immune dysregulation due to an underlying chronic kidney disease or cancer. Our study emphasizes the need for increased awareness of squamous cell carcinoma arising from epidermal cysts in patients with a history of cyst existence or recurrence, especially those with immune deficiencies. We expect these findings to contribute to early suspicion of malignant transformation and guide adequate clinical decision-making.

Immunophenotypic and Gene Expression Analyses of the Inflammatory Microenvironment in High-Grade Oral Epithelial Dysplasia and Oral Lichen Planus.

BACKGROUND: Oral lichen planus (OLP) and oral epithelial dysplasia (OED) present diagnostic challenges due to clinical and histologic overlap. This study explores the immune microenvironment in OED, hypothesizing that immune signatures could aid in diagnostic differentiation and predict malignant transformation. METHODS: Tissue samples from OED and OLP cases were analyzed using immunofluorescence/immunohistochemistry (IF/IHC) for CD4, CD8, CD163/STAT1, and PD-1/PDL-1 expression. RNA-sequencing was performed on the samples, and data was subjected to CIBERSORTx analysis for immune cell composition. Gene Ontology analysis on the immune differentially expressed genes was also conducted. RESULTS: In OED, CD8 + T-cells infiltrated dysplastic epithelium, correlating with dysplasia severity. CD4 + lymphocytes increased in the basal layer. STAT1/CD163 + macrophages correlated with CD4 + intraepithelial distribution. PD-1/PDL-1 expression varied. IF/IHC analysis revealed differential immune cell composition between OED and OLP. RNA-sequencing identified upregulated genes associated with cytotoxic response and immunosurveillance in OED. Downregulated genes were linked to signaling, immune cell recruitment, and tumor suppression. CONCLUSIONS: The immune microenvironment distinguishes OED and OLP, suggesting diagnostic potential. Upregulated genes indicate cytotoxic immune response in OED. Downregulation of TRADD, CX3CL1, and ILI24 implies dysregulation in TNFR1 signaling, immune recruitment, and tumor suppression. This study contributes to the foundation for understanding immune interactions in OED and OLP, offering insights into future objective diagnostic avenues.

MicroRNA copy number alterations in the malignant transformation of pleomorphic adenoma to carcinoma ex pleomorphic adenoma.

OBJECTIVE: This study used array comparative genomic hybridization to assess copy number alterations (CNAs) involving miRNA genes in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA), residual PA, and carcinoma ex pleomorphic adenoma (CXPA). MATERIALS AND METHODS: We analyzed 13 PA, 4 RPA, 29 CXPA, and 14 residual PA using Nexus Copy Number Discovery software. The miRNAs genes affected by CNAs were evaluated based on their expression patterns and subjected to pathway enrichment analysis. RESULTS: Across the groups, we found 216 CNAs affecting 2261 miRNA genes, with 117 in PA, 59 in RPA, 846 in residual PA, and 2555 in CXPA. The chromosome 8 showed higher involvement in altered miRNAs in PAs and CXPA patients. Six miRNA genes were shared among all groups. Additionally, miR-21, miR-455-3p, miR-140, miR-320a, miR-383, miR-598, and miR-486 were prominent CNAs found and is implicated in carcinogenesis of several malignant tumors. These miRNAs regulate critical signaling pathways such as aerobic glycolysis, fatty acid biosynthesis, and cancer-related pathways. CONCLUSION: This study was the first to explore CNAs in miRNA-encoding genes in the PA-CXPA sequence. The findings suggest the involvement of numerous miRNA genes in CXPA development and progression by regulating oncogenic signaling pathways.

Fibroblasts in Orchestrating Colorectal Tumorigenesis and Progression.

Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have been shown to possess critical functions in tumor progression. Although their roles predominantly have been described as tumor-promoting, more recent findings have identified subsets of CAFs with tumor-restraining functions. Accumulating evidence underscores large heterogeneity in fibroblast subsets in which distinct subsets differentially impact the initiation, progression, and metastasis of colorectal cancer. In this review, we summarize and discuss the evolving role of CAFs in colorectal cancer, highlighting the ongoing controversies regarding their distinct origins and multifaceted functions. In addition, we explore how CAFs can confer resistance to current therapies and the challenges of developing effective CAF-directed therapies. Taken together, we believe that, in this rapidly evolving field, it is crucial first to understand CAF dynamics comprehensively, and to bridge existing knowledge gaps regarding CAF heterogeneity and plasticity before further exploring the clinical targeting of CAFs.

MYC the oncogene from hell: Novel opportunities for cancer therapy.

Cancer comprises a heterogeneous disease, characterized by diverse features such as constitutive expression of oncogenes and/or downregulation of tumor suppressor genes. MYC constitutes a master transcriptional regulator, involved in many cellular functions and is aberrantly expressed in more than 70 % of human cancers. The Myc protein belongs to a family of transcription factors whose structural pattern is referred to as basic helix-loop-helix-leucine zipper. Myc binds to its partner, a smaller protein called Max, forming an Myc:Max heterodimeric complex that interacts with specific DNA recognition sequences (E-boxes) and regulates the expression of downstream target genes. Myc protein plays a fundamental role for the life of a cell, as it is involved in many physiological functions such as proliferation, growth and development since it controls the expression of a very large percentage of genes (∼15 %). However, despite the strict control of MYC expression in normal cells, MYC is often deregulated in cancer, exhibiting a key role in stimulating oncogenic process affecting features such as aberrant proliferation, differentiation, angiogenesis, genomic instability and oncogenic transformation. In this review we aim to meticulously describe the fundamental role of MYC in tumorigenesis and highlight its importance as an anticancer drug target. We focus mainly on the different categories of novel small molecules that act as inhibitors of Myc function in diverse ways hence offering great opportunities for an efficient cancer therapy. This knowledge will provide significant information for the development of novel Myc inhibitors and assist to the design of treatments that would effectively act against Myc-dependent cancers.

Global gene expression profile of proliferative verrucous leukoplakia and its underlying biological disease mechanisms.

BACKGROUND: Proliferative verrucous leukoplakia (PVL) is a rare and enigmatic oral potentially malignant disorder which almost invariably results in oral squamous cell carcinoma (OSCC). The aims of this project were to use transcriptome profiling to characterise PVL gene expression patterns for biomarker identification and gain insight into the molecular aetiopathogenesis of PVL. METHODS: Forty-three oral cavity mucosal biopsies from 32 patients with oral lesions clinically compatible with either PVL or non-PVL conventional oral leukoplakia (OLK) underwent transcriptome profiling by RNA sequencing. Data was analysed by hierarchical clustering, differential gene expression, functional enrichment and network analysis, sparse partial least squares discriminant analysis sPLS-DA, and immune cell phenotypic estimation. RESULTS: We found 464 genes significantly differentially expressed at least 2-fold between PVL and non-PVL OLK (193 up and 271 down). HOX genes, including HOXA1 and HOXB7, keratin-associated proteins (KRTAPs) and olfactory receptor G proteins (OR) were significantly upregulated in PVL. Other upregulated genes in PVL included FOS, WNT16 and IFNA1. Pathway analysis showed that there was a significant downregulation of connective tissue signalling in PVL. Classifying multivariate models based upon 22 genes discriminated PVL from non-PVL OLK. Bioinformatic profiling showed that immune cell profiles in PVL and OLK were similar except that fibroblast markers were reduced in PVL. CONCLUSION: These results demonstrate that PVL and conventional OLK are molecularly distinct with upregulation of many cancer-associated genes. They provide insight into the pathogenesis of PVL and show that biomarker based molecular diagnostics is feasible to discriminate and inform diagnosis and management.

Beyond genetics: driving cancer with the tumour microenvironment behind the wheel.

Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance.

The role of mitochondria in metastasis development.

Metastasis is a hallmark of cancer and is responsible for the largest number of cancer-related deaths. However, it remains poorly understood. Recently, evidence has accumulated pointing to the role of mitochondria in the metastatic spread of cancer cells. Mitochondria are dynamic organelles that have significant metabolic activity and are considered signaling centers with biosynthetic, bioenergetic, and signaling functions that control key biological pathways. Also, data were presented that mitochondria can influence all processes associated with oncogenesis, from malignant transformation to metastatic dissemination. The role of mitochondria in cancer progression/metastasis includes alteration of glycolysis, regulation of ROS, and suppression of intrinsic apoptosis. This review will summarize the current knowledge on the contribution of mitochondria to tumor cell invasion and dissemination and the possible mechanisms behind this. Mitochondrial-targeted therapeutic strategies to combat metastatic cancer will also be proposed.

Adenomyoepithelial adenosis mimicking phylloides: A diagnostic dilemma.

Benign proliferative breast diseases are well recognized in young females. Benign biphasic proliferation of epithelial and myoepithelial cells has been observed, among which adeno-myoepithelial adenosis is one of the rare morphologies published in the literature with the tendency to recur and poses a risk for low-grade malignant transformation. Here, we report a case of a young female who had a history of recurrent breast lump mimicking phyllodes tumor and eventually diagnosed as adeno-myoepithelial adenosis on histopathological examination. Benign proliferative breast diseases are well recognized in young females. Benign biphasic proliferation of epithelial and myoepithelial cells has been observed, among which adeno-myoepithelial adenosis is one of the rare morphologies published in the literature with the tendency to recur and poses a risk for low-grade malignant transformation. Here, we report a case of a young female who had a history of recurrent breast lump mimicking phyllodes tumor and eventually diagnosed as adeno-myoepithelial adenosis on histopathological examination.

Dickkopf 1 is expressed in normal fibroblasts during early stages of colorectal tumorigenesis.

BACKGROUND AND PURPOSE: Colorectal cancer progression from adenoma to cancer is a time-intensive process; however, the interaction between normal fibroblasts (NFs) with early colorectal tumors, such as adenomas, remains unclear. Here, we analyzed the response of the microenvironment during early tumorigenesis using co-cultures of organoids and NFs. MATERIALS AND METHODS: Colon normal epithelium, adenoma, cancer organoid, and NFs were established and co-cultured using Transwell inserts. Microarray analysis of NFs was performed to identify factors expressed early in tumor growth. Immunostaining of clinical specimens was performed to localize the identified factor. Functional analysis was performed using HCT116 cells. Serum DKK1 levels were measured in patients with colorectal cancer and adenoma. RESULTS: Colorectal organoid-NF co-culture resulted in increased organoid diameter and cell viability in normal epithelial and adenomatous organoids but not in cancer organoids. Microarray analysis of NFs revealed 18 genes with increased expression when co-cultured with adenoma and cancer organoids. Immunohistochemical staining revealed DKK1 expression in the tumor stroma from early tumor growth. DKK1 stimulation reduced HCT116 cell proliferation, while DKK1 silencing by siRNA transfection increased cell proliferation. Serum DKK1 level was significantly higher in patients with advanced cancer and adenoma than in controls. Serum DKK1 level revealed area-under-the-curve values of 0.78 and 0.64 for cancer and adenoma, respectively. CONCLUSION: These findings contribute valuable insights into the early stages of colorectal tumorigenesis and suggest DKK1 as a tumor suppressor. Additionally, serum DKK1 levels could serve as a biomarker to identify both cancer and adenoma, offering diagnostic possibilities for early-stage colon tumors. The present study has a few limitations. We considered using DKK1 as a candidate gene for gene transfer to organoids and NFs; however, it was difficult due to technical problems and the slow growth rate of NFs. Therefore, we used cancer cell lines instead. In addition, immunostaining and ELISA were based on the short-term collection at a single institution, and further accumulation of such data is desirable. As described above, most previous reports were related to advanced cancers, but in this study, new findings were obtained by conducting experiments on endoscopically curable early-stage tumors, such as adenomas.

Mature cystic ovarian teratoma with squamous cell carcinoma transformation: a case report and literature review.

OBJECTIVES: Cancerous transformation in mature cystic ovarian teratoma is rare. Herein, we reported a case of squamous cell carcinoma transformation in mature cystic ovarian teratoma and performed an in-depth literature review to highlight the risk factors, prognosis, and suggested treatment for these patients. CASE PRESENTATION: We report a 66-years old postmenopausal woman diagnosed with a 120×90 (mm) mass at the left adnexa compatible with mature cystic ovarian teratoma. Following resection, the histopathological investigations showed malignant transformation in her mature cystic ovarian teratoma, and the immunohistochemistry for cytokeratin (CK) 5/6 and tumor protein 63 (P63) indicated squamous cell carcinoma transformation. She has been observed for her stage IA tumor and has been cancer-free for 6 months. CONCLUSIONS: Although malignant transformation in mature cystic ovarian teratoma is rare, it should be suspected if certain risk factors, e.g., elderly and high tumor size, exist. Stage IA patients' prognosis is favorable, and chemotherapy is not recommended.

Copy Number Alterations Predict Development of OSCC from Oral Leukoplakia.

Oral leukoplakia (OLK) is a common type of potentially malignant disorder. Early identification of the malignancy potential leads to a better management of OLK and prediction of development of oral squamous cell carcinoma (OSCC). However, there has been no effective biomarker to assess the risk of malignancy in OLK. Genomic copy number alteration (CNA) is a complex chromosomal structural variation in the genome and has been identified as a potential biomarker in multiple cancers. This study aimed to develop a predictive model for the malignant transformation risk of OLK by copy number analysis. A total of 431 OLK samples with long-term follow-up (median follow-up of 67 mo) from multiple academic centers were analyzed for CNAs. CNA events increased with the severity of hyperplasia, mild dysplasia, moderate dysplasia, and severe dysplasia. More CNA events were present in patients with OLK who later developed OSCC than in those with OLK who did not. By multivariate Cox regression analysis, the OLK of the CNA scorehigh group showed an increased risk of malignant transformation than the CNA scorelow group (P < 0.001). A CNA score model was developed to accurately predict the prognosis (area under the receiver operating characteristic curve [AUC] = 0.879; 95% confidence interval [CI], 0.799-0.959) and was validated using data from 2 external centers (AUC = 0.836, 95% CI, 0.683-0.989; AUC = 0.876, 95% CI, 0.682-1.000), and all of them showed better prediction performances than histopathological grade in assessing the transformation risk of OLK. Furthermore, we performed CNA models among 4 subgroups of OLK with hyperplasia, mild dysplasia, moderate dysplasia, and severe dysplasia and found that CNA score can accurately predict malignant transformation of different subgroups. CNA score may be a useful biomarker to predict malignant transformation of OLK. Subtyping of OLK by the CNA score could contribute to better management of OLK and predicting development of OSCC.

Ribogenesis boosts controlled by HEATR1-MYC interplay promote transition into brain tumour growth.

Cell commitment to tumourigenesis and the onset of uncontrolled growth are critical determinants in cancer development but the early events directing tumour initiating cell (TIC) fate remain unclear. We reveal a single-cell transcriptome profile of brain TICs transitioning into tumour growth using the brain tumour (brat) neural stem cell-based Drosophila model. Prominent changes in metabolic and proteostasis-associated processes including ribogenesis are identified. Increased ribogenesis is a known cell adaptation in established tumours. Here we propose that brain TICs boost ribogenesis prior to tumour growth. In brat-deficient TICs, we show that this dramatic change is mediated by upregulated HEAT-Repeat Containing 1 (HEATR1) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High HEATR1 expression correlates with poor glioma patient survival and patient-derived glioblastoma stem cells rely on HEATR1 for enhanced ribogenesis and tumourigenic potential. Finally, we show that HEATR1 binds the master growth regulator MYC, promotes its nucleolar localisation and appears required for MYC-driven ribogenesis, suggesting a mechanism co-opted in ribogenesis reprogramming during early brain TIC development.