Biology subjects

VanBrocklin, M. W.

Publications and source records attributed to VanBrocklin, M. W..

5 recordsLinked to original sources

bioRxiv2026

Focal adhesion kinase promotes metastasis in BRAF-mutant melanoma

Despite the availability of several FDA-approved therapies, metastatic melanoma remains a significant clinical challenge, particularly for patients with brain metastases, which frequently represent the site of treatment failure and a major cause of melanoma-related mortality. Melanoma exhibits a strong propensity to metastasize to the brain, yet the molecular mechanisms driving this lethal progression remain incompletely understood, limiting the development of effective treatment options. Building on our prior discovery that focal adhesion kinase (FAK) is a key mediator of AKT1-driven brain metastasis, we sought to validate the role of FAK in melanoma progression and metastatic dissemination. Using complementary autochthonous and syngeneic mouse models of BRAF-mutant melanoma, we evaluated the impact of FAK expression on overall survival, primary tumor growth, and metastasis. Through the generation of targeted FAK mutants, we distinguished kinase-dependent from kinase-independent functions and demonstrate that FAK promotes melanoma metastasis in a kinase-dependent manner. Furthermore, we establish that FAK functions downstream of PTEN to drive metastatic progression. Collectively, these findings support the therapeutic potential of FAK inhibition, either alone or in combination with existing treatments, to more effectively combat metastatic melanoma and inform the development of emerging FAK-targeted therapies.

cancer biology↗

bioRxiv2024

Transdermal Delivery of Ultradeformable Cationic Liposomes Complexed with miR211-5p (UCL-211) Stabilizes BRAFV600E+ Melanocytic Nevi

Small non-coding RNAs (e.g. siRNA, miRNA) are involved in a variety of melanocyte-associated skin conditions and act as drivers for alterations in gene expression within melanocytes. These molecular changes can potentially affect the cellular stability of melanocytes and promote their oncogenic transformation. Thus, small RNAs can be considered as therapeutic targets for these conditions, however, their topical delivery to the melanocytes through the epidermal barrier is challenging. We synthesized and extensively evaluated ultradeformable cationic liposome (UCLs) carriers complexed with synthetic microRNAs (miR211-5p; UCL-211) for transdermal delivery to melanocytes. UCL-211 complexes were characterized for their physicochemical properties, encapsulation efficiency, and deformability, which revealed a significant advantage over conventional liposomal carriers. Increased expression of miR211-5p stabilizes melanocytic nevi and keeps them in growth-arrested state. We did a comprehensive assessment of cellular delivery, and biological activity of the miR211-5p carried by UCL-211 in vitro and their permeation through the epidermis of intact skin using ex vivo human skin tissue explants. We also demonstrated, in vivo, that topical delivery of miR211-5p by UCL-211 stabilized BRAFV600E+ nevi melanocytes in a benign nevi state.

pharmacology and toxicology↗

bioRxiv2023

Human Rhinoviruses: a novel class of oncolytic virus

While continuing to develop new and improved OVs, researchers have been vigilant in optimizing their ability to safely infect, replicate, and induce an immune response within tumors. There are currently two crucial limitations in OV development, however: modification of viruses often negatively impact their ability to infect, and induction of strong immune responses also promotes rapid viral clearance. In this study, we investigate wild-type HRVs as a novel class of OV. Multiple HRV serotypes were propagated in human melanoma cell lines to produce highly oncolytic populations of virus. A large panel of cancer types were infected, with cytotoxicity evaluated using flow cytometry and real time live imaging. Pro-inflammatory signaling was assessed by cytokine multiplexing. Tumor responses to HRV were assessed in human xenograft and in syngeneic, immune-competent mouse tumor models. We find that HRVs are capable of infecting and killing a wide variety of human cancer cell lines in vitro and in vivo, inducing pro-inflammatory responses and, ultimately, tumor regression. We propose that the natural safety profile of these viruses, coupled with their anti-tumor efficacy and multivalent potential seen in our preclinical model systems, make HRVs ideal candidates for development as oncolytic viruses for clinical testing. Simple SummaryThe idea of utilizing viruses to combat cancer has been around for over a century, yet in practice has seen relatively modest therapeutic success following decades of strategic design to improve safety, efficacy, and tumor selectivity. Engagement of an immune response is critical to have lasting tumor regression upon treatment, but many patients are unable to mount a sufficient response to standard-of-care immunotherapy alone. Oncolytic viruses (OVs) have been shown to synergize with such therapies to accomplish this goal to varying degrees. The purpose of this study is to investigate human rhinoviruses (HRVs) to establish their efficacy as a novel class of anti-cancer agents. We aim to use HRVs to promote longer lasting and more effective immune responses to tumors by fostering viral persistence and immune evasion, in addition to developing multivalent treatment strategies that enhance tumor regression by preventing tumor escape from viral infection.

immunology↗

bioRxiv2022

Genetic silencing of AKT induces melanoma cell death

Aberrant activation of the PI3K-AKT pathway is common in melanoma but efforts to drug this pathway have proven largely ineffective in patients. In this study, we observed that pharmacological inhibition of AKT was ineffective whereas genetic silencing of all three AKT paralogs significantly abrogated melanoma cell growth through effects on mTORC signaling. This phenotype could be rescued by overexpression of AKT but was dependent on kinase activity. Interestingly, expression of the serine/threonine kinase SGK1 was increased following genetic suppression of AKT but only expression of activated SGK1 could rescue the lethal effect of AKT knockdown. SGK1 also increases tumor growth and decreases survival in a BRAFV600E-driven mouse model of melanoma. Pharmacological inhibition of SGK and AKT reduced cell proliferation. These results demonstrate that SGK1 can compensate for AKT loss in this context and suggest that dual targeting of SGK1 and AKT may represent a novel therapeutic strategy in this disease. SIGNIFICANCEAlthough the AKT1, 2 & 3 genes encode: Bona fide oncoprotein kinases; well-validated downstream effectors of PI3-lipids and: pleiotropic regulators of numerous aberrant properties of cancer cells, their role in melanoma progression and/or maintenance is poorly understood. Here we explore the effects of genetic or pharmacological inhibitors of AKT1-3 and conclude that combined inhibition of AKT plus the related SGK protein kinases may be required to inhibit melanomagenesis.

cancer biology↗

bioRxiv2020

MicroRNAs Restrain Proliferation in BRAFV600E Melanocytic Nevi

Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arisen from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs - MIR211-5p and MIR328-3p - induced mitotic failure, genome duplication and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations.

cancer biology↗