ORCID Profile
0000-0002-2538-0455
Current Organisation
Tulane University
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Publisher: Springer Science and Business Media LLC
Date: 26-06-2008
Publisher: IEEE
Date: 2007
Publisher: Cold Spring Harbor Laboratory
Date: 11-06-2020
DOI: 10.1101/2020.06.09.141747
Abstract: Phenotypic heterogeneity of cancer cells plays a critical role in shaping treatment response. This type of heterogeneity is organized spatially with specific phenotypes, such as sharply demarcated clusters of proliferating and cell cycle-arrested cells, predominating within discrete domains within a tumor. What determines the occurrence of specific tumor cell phenotypes in distinct microdomains of solid cancers is poorly understood. Here, we show that in melanoma spatial organization of phenotypic heterogeneity is dictated by the expression and activity of MITF. We reveal that this lineage survival oncogene controls ECM composition and organization, and ROCK-driven mechanotransduction through focal adhesion maturation and actin cytoskeleton functionality. In turn, altered tumor microarchitecture and structural integrity impact tumor solid stress which then mediates phenotypic heterogeneity through p27 Kip1 . Rho-ROCK-myosin signaling is necessary to transmit the effect of the reciprocal cell-ECM regulation into phenotypic heterogeneity. Our findings place cell-ECM crosstalk as a central driver of phenotypic tumor heterogeneity. Phenotypic heterogeneity is a major culprit of cancer therapy failure. We demonstrate that phenotypic heterogeneity is controlled through tumor cell-ECM crosstalk resulting in altered tumor microarchitecture, mechanotransduction and Rho-ROCK-myosin signaling. Melanoma shares these physical properties with any solid cancer underscoring the importance of our findings for therapeutically targeting this phenomenon.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2015
DOI: 10.1158/1538-7445.AM2015-1420
Abstract: Melanoma is the leading cause of skin cancer-related death. Survival rates are high if the disease is diagnosed early, but drop precipitously at later stages. Small molecule inhibitor therapy has given robust responses in the clinic, but relapse is almost certain. This relapse may be due, in part, to tumor heterogeneity. Not only are there multiple cell types within a tumor, but cancer cells themselves can exhibit various phenotypes. This can be due to genotype variation or nutrient availability, and result in populations with different proliferative and invasive capabilities. As these cells display various behaviors, they could also respond to therapies uniquely. Understanding the molecular signature influencing different sub-populations is therefore crucial to design the most effective therapeutic regimen. The fluorescence ubiquitination cell cycle indicator (FUCCI) system, which delineates phases of the cell cycle by visual means, was employed to better understand melanoma tumor heterogeneity. Using this model, it was found that tumor xenografts grown in mice produce two cohorts. One that contained distinct clusters of either arrested or proliferating cells, and another that displayed a homogenous dispersion of proliferating cells throughout the breadth of the tumor. These cohorts were subsequently discovered to display either low or high levels of microphthalmia-associated transcription factor (MITF) expression, respectively. Additionally, loss of MITF by shRNA treatment resulted in conversion of the ability of melanoma cells to give rise to a homogenous xenograft, to instead produce a clustered tumor phenotype. Furthermore, in a 3D in vitro tumor spheroid model, MITF expression was predominantly found in the periphery of the spheroid, which corresponds with the region of highly proliferative cells. Forced over-expression of MITF within these spheroids results in loss of the distinct proliferative ring, and instead a homogenous growth pattern. Not only do spheroids express MITF around the perimeter, but also markers of the Epithelial to Mesenchymal Transition (EMT). These markers, such as Vimentin and Slug, also switch to become expressed homogenously upon high MITF expression. Surprisingly, the increased levels of EMT marker expression by MITF do not correlate to increased migration, and these spheroids in fact show reduced invasion into collagen. We are currently exploring what other means of cancer cell migration could trump an enhanced EMT phenotype and slow invasion in our model. These data outline how tumor heterogeneity, including proliferative and invasive potential, is tightly intertwined with MITF expression, making it an important marker for therapy design. Citation Format: Crystal A. Tonnessen, Kimberley A. Beaumont, David S. Hill, Sheena M. Daignault, Andrea Anfosso, Russell J. Jurek, Wolfgang Weninger, Nikolas K. Haass. MITF regulates proliferative subpopulation tumor architecture and modifies invasion and characteristics of the epithelial to mesenchymal transition within melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research 2015 Apr 18-22 Philadelphia, PA. Philadelphia (PA): AACR Cancer Res 2015 (15 Suppl):Abstract nr 1420. doi:10.1158/1538-7445.AM2015-1420
Publisher: Elsevier BV
Date: 08-2018
Publisher: Informa UK Limited
Date: 10-12-2020
Publisher: Cold Spring Harbor Laboratory
Date: 09-2013
Abstract: The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and erse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53 ΔCTD/ΔCTD mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53 ΔCTD/ΔCTD mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus d ens p53 activity. Increased senescence in the Trp53 ΔCTD/ΔCTD bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53 ΔCTD induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53 ΔCTD has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53 ΔCTD showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.
Publisher: Springer Berlin Heidelberg
Date: 2015
Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2012
Abstract: The p53 tumor suppressor protein is a transcription factor that exerts its effects on the cell cycle via regulation of gene expression. Although the mechanism of p53-dependent transcriptional activation has been well-studied, the molecular basis for p53-mediated repression has been elusive. The E2F family of transcription factors has been implicated in regulation of cell cycle-related genes, with E2F6, E2F7, and E2F8 playing key roles in repression. In response to cellular DNA damage, E2F7, but not E2F6 or E2F8, is up-regulated in a p53-dependent manner, with p53 being sufficient to increase expression of E2F7. Indeed, p53 occupies the promoter of the E2F7 gene after genotoxic stress, consistent with E2F7 being a novel p53 target. Ablation of E2F7 expression abrogates p53-dependent repression of a subset of its targets, including E2F1 and DHFR, in response to DNA damage. Furthermore, E2F7 occupancy of the E2F1 and DHFR promoters is detected, and expression of E2F7 is sufficient to inhibit cell proliferation. Taken together, these results show that p53-dependent transcriptional up-regulation of its target, E2F7, leads to repression of relevant gene expression. In turn, this E2F7-dependent mechanism contributes to p53-dependent cell cycle arrest in response to DNA damage.
Publisher: Springer Berlin Heidelberg
Date: 2012
Publisher: Cold Spring Harbor Laboratory
Date: 23-11-2016
Publisher: Springer US
Date: 2007
Publisher: Rockefeller University Press
Date: 17-09-2019
Abstract: In chemotherapy-treated breast cancer, wild-type p53 preferentially induces senescence over apoptosis, resulting in a persisting cell population constituting residual disease that drives relapse and poor patient survival via the senescence-associated secretory phenotype. Understanding the properties of tumor cells that allow survival after chemotherapy treatment is paramount. Using time-lapse and confocal microscopy to observe interactions of cells in treated tumors, we show here that chemotherapy-induced senescent cells frequently engulf both neighboring senescent or nonsenescent tumor cells at a remarkable frequency. Engulfed cells are processed through the lysosome and broken down, and cells that have engulfed others obtain a survival advantage. Gene expression analysis showed a marked up-regulation of conserved macrophage-like program of engulfment in chemotherapy-induced senescent cell lines and tumors. Our data suggest compelling explanations for how senescent cells persist in dormancy, how they manage the metabolically expensive process of cytokine production that drives relapse in those tumors that respond the worst, and a function for their expanded lysosomal compartment.
Location: United States of America
Location: United States of America
No related grants have been discovered for Crystal Tonnessen-Murray.