miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. In melanoma, miRNAs can impair or ...facilitate a wide array of processes, and here we will focus on: the epithelial to mesenchymal transition (EMT), the immune milieu, and metabolism. Multiple miRNAs can affect the EMT process, even at a distance, for example through exosome-mediated mechanisms. miRNAs also strongly act on some components of the immune system, regulating the activity of key elements such as antigen presenting cells, and can facilitate an immune evasive/suppressive phenotype. miRNAs are also involved in the regulation of metabolic processes, specifically in response to hypoxic stimuli where they can mediate the metabolic switch from an oxidative to a glycolytic metabolism. Overall, this review discusses and summarizes recent findings on miRNA regulation in the melanoma tumor microenvironment, analyzing their potential diagnostic and therapeutic applications.
Cancer immunotherapy has shown impressive clinical results in the last decade, improving both solid and hematologic cancer patients’ overall survival. Nevertheless, most of the molecular aspects ...underlying the response to this approach are still under investigation. miRNAs in particular have been described as regulators of a plethora of different immunologic processes and thus have the potential to be key in the future developments of immunotherapy. In this review, we summarize and discuss the emerging role of miRNAs in the diagnosis and therapeutics of the four principal cancer immunotherapy approaches: immune checkpoint blockade, adoptive cell therapy, cancer vaccines, and cytokine therapy. In particular, this review is focused on potential roles for miRNAs to be adjuvants in soluble factor- and cell-based therapies, with the aim of helping to increase specificity and decrease toxicity, and on the potential for rationally identified miRNA-based diagnostic approaches to aid in precision clinical immunooncology.
Opinion statement
Biliary tract cancers are relatively uncommon, have an aggressive disease course and a dismal clinical outcome. Until recently, there have been very few clinical advances in the ...management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy. The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease. Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice. Mutation profiling has highlighted the genomic differences between the intra, extrahepatic cholangiocarcinoma, and gallbladder cancer. The mutational spectrum of intrahepatic cholangiocarcinoma differs according to geographic location and ethnicity. There is a higher incidence of chromatin modulating gene mutations in Western patients as compared with Asian patients with liver fluke-associated cholangiocarcinoma.
KRAS
and
p53
mutations are associated with an aggressive disease prognosis while
FGFR
mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma.
FGFR
and
IDH
mutations have promising agents in clinical trials at this time. An estimated 15 % of gallbladder cancers have
Her2/neu
amplification and can be targeted by trastuzumab. On the other hand, an estimated 10–15 % of cholangiocarcinomas have DNA repair mutations and may be candidates for immune therapies with checkpoint inhibitors. The promise of targeted therapies for biliary tract cancers can be fulfilled with well-designed, prospective, and multi-center clinical trials.
Melanoma is entering into an era of combinatorial approaches to build upon recent clinical breakthroughs achieved by novel single-agent therapies. One of the leading targets to emerge from the ...growing understanding of the molecular pathogenesis, heterogeneity, and resistance mechanisms of melanomas is the phosphoinositide 3-kinase (PI3K)-AKT pathway. Multiple genetic and epigenetic aberrations that activate this pathway have been identified in melanomas de novo and in acquired resistance models. These developments have been paralleled by the establishment of models for preclinical testing and the availability of compounds that target various effectors in the pathway. Thus, in addition to having a strong rationale for targeting, the PI3K-AKT pathway presents an immediate clinical opportunity. However, the development of effective strategies against this pathway must overcome several key challenges, including optimizing patient selection, overcoming feedback loops, and pathway cross-talk that can mediate resistance. This review discusses the current understanding and ongoing research about the PI3K-AKT pathway in melanoma and emerging strategies to achieve clinical benefit in patients by targeting it.
A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of ...effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The study and comprehension of the molecular mechanisms underlying cancer biology strongly rely on mouse modeling. An ideal mouse model should have molecular, histopathological, and etiological ...characteristics as close as possible to those of the corresponding human tumors. Among solid tumors, colorectal cancer (CRC) is one of the malignancies that best suits reproduction in an animal model: it evolves through a progressive set of molecular events and is generally associated with a precise histopathology and a neat cataloging of stages and grades. The development of refined CRC mouse models over several decades has seen them recently evolve toward sophisticated systems that ever more closely approximate the human pathology, with different models addressing different human CRC subtypes. In particular, a metastatic CRC model has been seen as a "holy grail" in this field, and we describe in this review the path taken to achieve metastatic models and discuss the path forward.
Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the
gene. To understand the role of oncogenic
in CRC, we engineered a mouse model of ...metastatic CRC that harbors an inducible oncogenic
allele (
) and conditional null alleles of
and
(iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the
allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated
signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of
-driven invasiveness. Genetic extinction of
resulted in specific elimination of the
subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease
This faithful CRC model provides genetic evidence that
drives CRC invasion and maintenance of metastases.
Genetically engineered mouse models (GEMMs) of cancer have affected virtually all areas of cancer research. However, the accelerated discovery of new cancer genes emerging from large-scale cancer ...genomics and new chemical entities pouring from the drug discovery pipeline have strained the capacity of traditional germline mouse models to provide crucial insights. This Review introduces new approaches to modelling cancer, with emphasis on a growing collection of non-germline GEMMs (nGEMMs). These offer flexibility, speed and uniformity at reduced costs, thus paving the way for much needed throughput and practical preclinical therapeutic testing models.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background and Aims
Cholangiocarcinoma (CCA) is a deadly and highly therapy‐refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. ...Whereas recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal actionable insights.
Approach and Results
Here, we have integrated immune checkpoint‐directed immunohistochemistry with next‐generation sequencing of resected intrahepatic CCA samples from 96 patients. We found that both T‐cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center. Using two approaches, we identify high programmed cell death protein 1 or lymphocyte‐activation gene 3 and low CD3/CD4/inducible T‐cell costimulator specifically in the tumor center as associated with poor survival. Moreover, loss‐of‐function BRCA1‐associated protein‐1 mutations are associated with and cause elevated expression of the immunosuppressive checkpoint marker, B7 homolog 4.
Conclusions
This study provides a foundation on which to rationally improve and tailor immunotherapy approaches for this difficult‐to‐treat disease.
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