identification-histological-characterization-dissection-mouse

Identification, Histological Characterization, and Dissection of Mouse Prostate Lobes for In Vitro 3D Spheroid Culture Models

Genetically engineered mouse models (GEMMs) serve as effective pre-clinical models for investigating most types of human cancers, including prostate ...

SUNY Upstate Medical University

Prostate cancer is one of the most common malignancies affecting men worldwide. High mortality rates from advanced and metastatic prostate cancer in the United States are contrasted by a relatively indolent course in the majority of cases. This gives hope for finding methods that could direct personalized diagnostic, preventative, and treatment approaches to patients with prostate cancer. Recent advances in multiparametric magnetic resonance imaging (MP-MRI) offer a noninvasive diagnostic intervention which allows correlation of prostate tumor image characteristics with underlying biologic evidence of tumor progression. The power of MP-MRI includes examination of both local invasion and nodal disease and might overcome the challenges of analyzing the multifocal nature of prostate cancer. Future directions include a careful analysis of the genomic signature of individual prostatic lesions utilizing image-guided biopsies. This review examines the diagnostic potential of MRI in prostate cancer.

Defining the radiobiology of prostate cancer progression: An important question in translational prostate cancer research.

Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence. Further analysis of primary vs. castration resistant prostate cancer indicate that disruption of WAVE complex gene expression, and particularly WAVE1 gene (WASF1) loss, is also associated with castration resistance, where WASF1 is frequently co-deleted with PTEN and resists androgen deprivation therapy (ADT). Hence, we propose that WASF1 status defines a subtype of ADT-resistant patients. Better understanding of the effects of WAVE pathway disruption will lead to development of better diagnostic and treatment modalities. 

Loss of Wave1 gene defines a subtype of lethal prostate cancer.

Crk is the prototypical member of a class of Src homology 2 (SH2) and Src homology 3 (SH3) domain-containing adaptor proteins that positively regulate cell motility via the activation of Rac1 and, in certain tumor types such as GBM, can promote cell invasion and metastasis by mechanisms that are not well understood. Here we demonstrate that Crk, via its phosphorylation at Tyr251, promotes invasive behavior of tumor cells, is a prominent feature in GBM, and correlating with aggressive glioma grade IV staging and overall poor survival outcomes. At the molecular level, Tyr251 phosphorylation of Crk is negatively regulated by Abi1, which competes for Crk binding to Abl and attenuates Abl transactivation. Together, these results show that Crk and Abi1 have reciprocal biological effects and act as a molecular rheostat to control Abl activation and cell invasion. Finally, these data suggest that Crk Tyr251 phosphorylation regulate invasive cell phenotypes and may serve as a biomarker for aggressive GBM. 

Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma.

Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men.

Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers.

Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors neither have curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of  in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF.  loss resulted in a significant increase in the activity of the Src Family Kinases (SFKs), STAT3 and NF-κB signaling. We also observed impairment of hematopoietic stem cells self-renewal and fitness, as evidenced in non-competitive and competitive bone marrow transplant experiments. CD34+ hematopoietic progenitors and granulocytes from patients with PMF showed decreased levels of  transcript as well as increased activity of SFKs, STAT3 and NF-κB. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-κB signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF.

Article	Year
Defining the radiobiology of prostate cancer progression: An important question in translational prostate cancer research. Experimental biology and medicine (Maywood, N.J.)\| PubMed ID: 24879423	2014
Loss of Wave1 gene defines a subtype of lethal prostate cancer. Oncotarget\| PubMed ID: 25906751	2015
Reciprocal regulation of Abl kinase by Crk Y251 and Abi1 controls invasive phenotypes in glioblastoma. Oncotarget\| PubMed ID: 26473374	2015
Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers. The Prostate\| PubMed ID: 27225637	2016
Bone marrow-specific loss of induces myeloproliferative neoplasm with features resembling human myelofibrosis. Blood\| PubMed ID: 30213875	2018

Leszek Kotula

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