Search

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Most pancreatic ductal adenocarcinoma (PDAC) develops from pancreatic epithelial cells bearing activating mutant KRAS genes through precancerous lesions, i.e. acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). During pancreatic tumorigenesis, Hes1 expression starts with the transition from acinar cells to ADM, and continues during PanIN and PDAC formation, but the role of Hes1 in pancreatic tumorigenesis is not fully elucidated. Here we show that Hes1 plays an essential role in the initiation and progression of KRAS-driven pancreatic tumorigenesis. In vitro, activation of MAPK signaling due to EGF or mutant KRAS activation induced sustained Hes1 expression in pancreatic acinar cells. In vivo, acinar cell-specific activation of mutant KRAS by Elastase1-CreERT2;Kras G12D induced ADM/PanIN formation with Hes1 expression in mice, and genetic ablation of Hes1 in these mice dramatically suppressed PanIN formation. Gene expression analysis and lineage tracing revealed that Hes1 regulates acinar-to-ductal reprogramming-related genes and, in a Hes1-deficient state, mutant Kras-induced ADM could not progress into PanIN, but re-differentiated into acinar cells. In the Elastase1-CreERT2;Kras G12D ;Trp53 R172H mouse PDAC model, genetic ablation of Hes1 completely blocked PDAC formation by keeping PanIN lesions in low-grade conditions, in addition to reducing the occurrence of PanIN. Together, these findings indicate that mutant KRAS-induced Hes1 plays an essential role in PDAC initiation and progression by regulating acinar-to-ductal reprogramming-related genes.

Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity., (© 2022. The Author(s).)

Hepatoid adenocarcinoma of the stomach (HAS), a rare subtype of gastric cancer (GC), has a low incidence but a high mortality rate. Little is known about the molecular features of HAS. Here we applied whole-exome sequencing (WES) on 58 tumours and the matched normal controls from 54 HAS patients, transcriptome sequencing on 30 HAS tumours, and single-cell RNA sequencing (scRNA-seq) on one HAS tumour. Our results reveal that the adenocarcinomatous component and hepatocellular-like component of the same HAS tumour originate monoclonally, and HAS is likely to initiate from pluripotent precursor cells. HAS has high stemness and high methionine cycle activity compared to classical GC. Two genes in the methionine cycle, MAT2A, and AHCY are potential targets for HAS treatments. We provide the first integrative genomic profiles of HAS, which may facilitate its diagnosis, prognosis, and treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The development and progression of solid tumors is dependent on cancer cell autonomous drivers and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the TME possess both tumor-promoting and tumor-restraining functions. In the current study, we interrogated the role of αSMA + CAFs in a genetic mouse model of metastatic colorectal cancer (CRC). Selective depletion of αSMA + CAFs resulted in increased tumor invasiveness, lymph node metastasis, and reduced overall survival. Depletion of αSMA + CAFs reduced BMP4 and increased TGFβ1 secretion from stromal cells, and was associated with increased Lgr5 + cancer stem-like cells (CSCs) and the generation of an immunosuppressive TME with increased frequency of Foxp3 + regulatory T cells and suppression of CD8 + T cells. This study demonstrates that αSMA + CAFs in CRC exert tumor-restraining functions via BMP4/TGFβ1 paracrine signaling that serves to suppress Lgr5 + CSCs and promote anti-tumor immunity, ultimately limiting CRC progression.

Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. The survival outcomes remain poor for patients with relapsed or metastatic disease. Effective targeted therapy is lacking due to our limited knowledge of the underlying cellular and molecular mechanisms leading to disease progression. In this study, we used functional assays in vitro and in vivo (zebrafish and xenograft mouse models) to demonstrate the crucial role of HDAC6, a cytoplasmic histone deacetylase, in driving RMS tumor growth, self-renewal, and migration/invasion. Treatment with HDAC6-selective inhibitors recapitulates the HDAC6 loss-of-function phenotypes. HDAC6 regulates cytoskeletal dynamics to promote tumor cell migration and invasion. RAC1, a Rho family GTPase, is an essential mediator of HDAC6 function, and is necessary and sufficient for RMS cell migration and invasion. High expression of RAC1 correlates with poor clinical prognosis in RMS patients. Targeting the HDAC6-RAC1 axis represents a promising therapeutic option for improving survival outcomes of RMS patients.

There is no unique formula for angiogenesis. Instead there is a large group of potential participating proteins that interact in complex ways. Depending upon the surrounding cell types and the relative expression levels of angiogenesis-related proteins, the ‘angiogenesis cascade’ can vary. Therefore, it is valuable to study and compare the role of proteins in several well-characterized vascular beds. The eye provides a useful model system, because it contains several vascular beds sandwiched between avascular tissue. This allows for unequivocal identification and quantitation of new vessels. Retina-specific promoters combined with inducible promoter systems provide a means to regulate the expression of proteins of interest. As a relatively isolated compartment, the eye also provides advantages for gene transfer. By gaining insight regarding the molecular signals involved in various types of ocular angiogenesis, general concepts can emerge that may apply to other settings, including tumor angiogenesis. One concept that has emerged is that despite participation of multiple stimulatory factors for ocular neovascularization, VEGF plays an essential role and interruption of VEGF signaling is an important therapeutic strategy. Another concept is that while most studies have focused on prevention of ocular neovascularization, regression of new vessels is desirable and is achievable with at least three agents, combretastatin A-4 phosphate, pigment epithelium-derived factor, and angiopoietin-2. Finally, endostatin and angiostatin, which have been sources of controversy because of inconsistent results in tumor models, have been shown to have good efficacy when delivered by gene transfer in models of ocular neovascularization. These results provide leads for new ocular treatments and perspective for evaluation of studies of neovascularization in extraocular tissues.Oncogene (2003) 22, 6537-6548. doi:10.1038/sj.onc.1206773 [ABSTRACT FROM AUTHOR]