https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

The basics of epithelial-mesenchymal transition

The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of “hallmark” gene sets as part of MSigDB. Each hallmark in this collection consists of a “refined” gene set, derived from multiple “founder” sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis.

https://www.cell.com/cell-systems/pdf/S2405-4712(15)00218-5.pdf

The Molecular Signatures Database Hallmark Gene Set Collection

As appreciation grows for the contribution of the tumor microenvironment to the progression of cancer, new evidence accumulates to support that the participation of stromal cells can extend beyond the local environment. Recently, Elkabets and colleagues demonstrated a systemic interaction between cancer cells and distant bone marrow cells to support the growth of otherwise indolent tumor cells at a secondary site, raising thought-provoking questions regarding the involvement of stromal cells in maintaining metastatic dormancy.

Waking up dormant tumors

Provided herein are compositions of lipid-based nanoparticles, such as exosomes, that comprise a therapeutic agent that inhibits the activity of an oncogene. Also provided are methods of using such compositions to treat a patient having a cancer caused by the activation of the oncogene. In particular, exosomes comprising an siRNA that targets oncogenic Myc are provided along with methods of their use in treating cancer.

Therapeutic targeting of oncogenes using exosomes

Most of the present knowledge on the pathomechanism of renal fibrosis is based on experimental studies with laboratory animals. Today, a variety of genetic and inducible animal models that mimic primary causes of human disease, such as diabetes mellitus, glomerulonephritis or lupus erythematodes are available. However, only few of these models progress consistently to interstitial fibrosis in the kidney involving interestitial fiberosis, tubular atrophy and glomerulosclerosis, common features of renal fibrogenesis. In this chapter, three different mouse models of human kidney disease are described highlighting their utility to study pathways leading to renal fibrosis.

Experimental Models to Study the Origin and Role of Myofibroblasts in Renal Fibrosis

Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1 to α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied. We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in contrast with its human ortholog, contains an additional cysteine residue and lacks the M93 and K211 residues involved in sulfilimine bond formation between adjacent protomers. This may alter α4 chain interactions with other α chains, as supported by temporal and anatomic expression patterns of collagen IV chains during zebrafish development. Despite the divergence between zebrafish and human α3 NC1 domain (endogenous angiogenesis inhibitor, Tumstatin), the zebrafish α3 NC1 domain exhibits conserved anti-angiogenic activity in human endothelial cells. Our work supports type IV collagen is largely conserved between zebrafish and humans, with a possible difference involving the α4 chain.

/pdf/identification-of-unique-a4-chain-structure-and-conserved-3aofcciq.pdf

Identification of unique α4 chain structure and conserved anti-angiogenic activity of α3NC1 type IV collagen in zebrafish


 Homozygous deletion of MTAP occurs in about 15% of all human cancers, such as glioblastoma, pancreatic cancer, mesothelioma, urothelial bladder carcinoma, and lung squamous cell carcinoma. PRMT5 inhibitors show activity against MTAP-deleted cancer cells in culture and xenografts with a mechanism that relies on the significant elevation of the MTAP substrate, methylthioadenosine (MTA). Previously, we have shown that unlike cells in culture, MTA levels in MTAP-deleted primary human GBM tumors are not significantly higher than in MTAP-intact tumors. Therefore, combining the PRMT5 inhibitor with another drug may be required to increase the therapeutic window and clinical efficacy of a PRMT5 inhibitor in MTAP-deleted patients. Here, we identified a natural small molecular chemical compound with a good safety profile that synergizes with a PRMT5-MTA complex inhibitor, which boosts the efficacy of MTAP-deleted selective cell killing in the presence of MTA sequestering cells. This combination therapy significantly increases the potency of PRMT5 inhibitor treatment in MTAP-deleted cells across various tumor cell lines and lowers the IC50 of PRMT5 inhibitor treatment. In vivo, PRMT5 inhibitor combination treatment leads to smaller tumor volumes in MTAP-deleted CDX tumors (U87, glioma cell line) compared to PRMT5 inhibitor monotherapy. In summary, our proposed combination therapy of PRMT5 inhibition with a natural compound may increase the therapeutic window and clinical efficacy of PRMT5 inhibitors leading to better treatment options for patients harboring MTAP-deleted cancer.
 Citation Format: Yasaman Barekatain, Kyle LaBella, Hikaru Sugimoto, Kristen Harris, Sunada Khadka, Florian Muller, Raghu Kalluri. PRMT5 inhibition synergizes with a natural small molecule compound to kill MTAP-deleted cells and suppress tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1073.

Raghu Kalluri

Papers

Waking up dormant tumors

Therapeutic targeting of oncogenes using exosomes

Experimental Models to Study the Origin and Role of Myofibroblasts in Renal Fibrosis

Identification of unique α4 chain structure and conserved anti-angiogenic activity of α3NC1 type IV collagen in zebrafish

Abstract 1073: PRMT5 inhibition synergizes with a natural small molecule compound to kill MTAP-deleted cells and suppress tumor growth