Publications by authors named "Anil Rustgi"

Article Synopsis
  • - The study investigates how certain mutations in the p53 protein can lead to increased cancer cell invasion, contradicting previous views on mutant p53's role in cancer progression.
  • - Researchers found that mutant p53 enhances the ability of cancer cells to invade their surroundings by modulating the RhoA/ROCK signaling pathway and affecting the organization of the extracellular matrix (ECM).
  • - The findings suggest that the invasive effects of mutant p53 are influenced not just by the cells themselves but also by the mechanical properties of the ECM, highlighting the complex interactions during cancer metastasis.
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Article Synopsis
  • Aberrant cell fate transitions can lead to cancer, and p63 is identified as a key factor in determining cell type in esophageal development, specifically between squamous and neuroendocrine lineages.
  • Deleting p63 in developing mice and human stem cells leads to increased neuroendocrine differentiation, suggesting that this transcription factor is crucial for maintaining proper cell identity.
  • In esophageal neuroendocrine carcinoma, p63 is silenced by EZH2-mediated trimethylation, but reactivating p63 can promote a return to squamous cell characteristics, highlighting its role in cancer progression.
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Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during Kras acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing Kras.

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  • Esophageal squamous cell carcinoma (ESCC) is primarily caused by environmental factors like alcohol and tobacco, but it can also arise from rare non-environmental conditions that are often overlooked.
  • The review emphasizes the necessity for healthcare professionals to recognize these rare diseases (like Fanconi anemia and achalasia) as high-risk for developing ESCC, advocating for early detection through endoscopic evaluation and advanced imaging techniques.
  • It highlights common underlying mechanisms of malignant transformation in these conditions, such as abnormal cell growth, inflammation, and genetic instability, to improve understanding and screening strategies for ESCC.
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  • The study investigates the relationship between systemic bile acids and the progression of Barrett's esophagus (BE), particularly their role in advancing stages that may lead to esophageal adenocarcinoma (EAC).
  • It involved profiling serum bile acids in 141 subjects (both with and without BE) and examined how various factors, like diet and age, influenced bile acid levels, finding significant differences between non-BE and BE stages.
  • Results indicate that higher levels of specific bile acids, especially cholic acid, are linked to advanced BE conditions and gene expression changes, suggesting that they may serve as potential biomarkers or targets for future therapeutic strategies.
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  • Researchers have discovered that Mdm2 and MdmX, known for regulating the p53 tumor suppressor, also play significant roles in cellular processes unrelated to p53, particularly in cell migration and invasion.
  • In experiments with cells lacking p53, reducing Mdm2 or MdmX, as well as inhibiting their complex, negatively impacted cell movement, spreading, and attachment, and decreased metastasis in live models.
  • The study highlights that Mdm2 represses the expression of Sprouty4, which is essential for its regulation of migration and adhesion, indicating a new mechanism influencing cancer cell behavior independent of p53.
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Endoplasmic reticulum to mitochondria Ca transfer is important for cancer cell survival, but the role of mitochondrial Ca uptake through the mitochondrial Ca uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, deletion ( ) ablated mitochondrial Ca uptake, which reduced proliferation and inhibited self-renewal.

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The p53 tumor suppressor protein has a plethora of cell-intrinsic functions and consequences that impact diverse cell types and tissues. Recent studies are beginning to unravel how wild-type and mutant p53 work in distinct ways to modulate tumor immunity. This sets up a disequilibrium between tumor immunosurveillance and escape therefrom.

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Introduction: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease.

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Article Synopsis
  • Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal cancer with most cases being diagnosed at an advanced stage, and there's no recommended population-wide screening despite some benefits from monitoring high-risk individuals.
  • This study aimed to compare survival rates of patients who detected their PDAC through surveillance with a national database, using data from the Cancer of the Pancreas Screening program and matched SEER patients.
  • Results showed that individuals in the screening group were diagnosed at an earlier stage with smaller tumor sizes compared to the control group, but overall survival benefits remain uncertain and require further investigation.
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We have found that the ketogenic (Keto) diet is able to, unexpectedly, promote the metastatic potential of cancer cells in complementary mouse models. Notably, the Keto diet-induced tumor metastasis is dependent on BTB domain and CNC homolog 1 (BACH1) and its up-regulation of pro-metastatic targets, including cell migration-inducing hyaluronidase 1, in response to the Keto diet. By contrast, upon genetic knockout or pharmacological inhibition of endogenous BACH1, the Keto diet-mediated activation of those targets is largely diminished, and the effects on tumor metastasis are completely abolished.

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Despite the promising outcomes of immune checkpoint inhibitors (ICIs), resistance to ICI presents a new challenge. Therefore, selecting patients for specific ICI applications is crucial for maximizing therapeutic efficacy. Herein, we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC.

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Cancer-associated fibroblasts (CAFs), a heterogenous population, can promote cancer cell proliferation, migration, invasion, immunosuppression, and therapeutic resistance in solid tumors. These effects are mediated through secretion of cytokines and growth factors, remodeling of the extracellular matrix, and providing metabolic support for cancer cells. The presence of CAFs in esophageal carcinoma are associated with reduced overall survival and increased resistance to chemotherapy and radiotherapy; thus, identifying therapeutic vulnerabilities of CAFs is a necessity.

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The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro.

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Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying protumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis.

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The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3).

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While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of squamous versus neuroendocrine lineage in esophageal development and malignancy. Deletion of results in extensive neuroendocrine differentiation in the developing mouse esophagus and esophageal progenitors derived from human embryonic stem cells.

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Unlabelled: TP53 mutations are frequent in esophageal squamous cell carcinoma (ESCC) and other SCCs and are associated with a proclivity for metastasis. Here, we report that colony-stimulating factor-1 (CSF-1) expression is upregulated significantly in a p53-R172H-dependent manner in metastatic lung lesions of ESCC. The p53-R172H-dependent CSF-1 signaling, through its cognate receptor CSF-1R, increases tumor cell invasion and lung metastasis, which in turn is mediated in part through Stat3 phosphorylation and epithelial-to-mesenchymal transition (EMT).

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Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1β transgenic mice, expressing human interleukin (IL)-1β in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett's esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1β-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive.

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The mitochondrial uniporter (MCU) Ca ion channel represents the primary means for Ca uptake by mitochondria. Mitochondrial matrix Ca plays critical roles in mitochondrial bioenergetics by impinging upon respiration, energy production and flux of biochemical intermediates through the TCA cycle. Inhibition of MCU in oncogenic cell lines results in an energetic crisis and reduced cell proliferation unless media is supplemented with nucleosides, pyruvate or α-KG.

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The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B.

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Background & Aims: Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown.

Methods: Using CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) in murine esophageal organoids. Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing.

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The mitochondrial uniporter (MCU) Ca ion channel represents the primary means for Ca uptake into mitochondria. Here we employed and models with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblasts was associated with increased MCU expression, enhanced mitochondrial Ca uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca -dependent stimulation of mitochondrial respiration.

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