Linda J Metheny-Barlow, Ph.D.
Regulation of Vascular Integrity and Metastasis My long-term research interests include the regulation of angiogenesis and the role of vascular mural cells (pericytes and smooth muscle cells) in the breast tumor microenvironment. My previous work has demonstrated that mural cells can respond directly to angiopoietin-1 to help stabilize the breast tumor vasculature. More recently, we have used in vitro co-culture models to analyze paracrine interactions between mural cells, endothelial cells, and breast cancer cells in order to identify critical tumor-induced alterations in mural cell function that may contribute to the maturation defect exhibited by the tumor vasculature. We have determined that functional gap junction protein Connexin 43 (Cx43) is required for proper stabilizing interactions between mural cells and endothelial cells, and that tumor cells downregulate or inactivate mural cell Cx43 to elicit endothelial proliferation in co-cultures. Furthermore, tumor angiogenesis proceeds more rapidly on a Cx43-deficient host background, with decreased pericyte investiture of tumor vessels. Of particular interest, this decreased vessel stabilization is associated with an increase in metastasis to the lung in the Cx43-deficient host. Our ongoing studies seek to better define the factors leading to Cx43 dysregulation in tumor vessels, and the role of mural/vascular cell Cx43 in inhibition of metastasis. Molecular Determinants of Breast Cancer Metastasis to Brain A second major interest in my lab is the development and characterization of models to study breast cancer brain metastasis development and treatment, with a focus on tumor-brain microenvironment interactions. We have developed two syngeneic rodent models of breast cancer brain metastasis which we are using to identify potential targets for therapeutic intervention, as well as to assess their effects on the brain vasculature and interactions with microglia. Our current efforts are addressed at defining the role of autocrine and paracrine brain derived neurotrophic factor (BDNF)-p75NTR signaling in breast cancer metastasis to the brain, and the testing of therapeutics to mitigate this signaling to prevent or treat brain metastases. Radiation Modifiers for Brain Metastasis: Effects on Tumor Response, Brain Injury and Cognition Since radiation therapy is the primary modality for treatment of brain metastases, we have extended our studies to include the therapeutic tumor and normal tissue responses to radiation. Although fractionated whole brain irradiation (fWBI) can be successfully used to achieve tumor control of brain metastatic disease, patients surviving longer than six months are frequently afflicted with a progressive, irreversible cognitive impairment resulting from the therapy. We seek to better define the mechanisms by which radiation injures the normal brain, and identify compounds that can mitigate radiation-induced normal brain injury without adversely impacting therapeutic response to the tumor. We are currently investigating the use of cognition-sparing Peroxisomal Proliferator-Activated Receptor (PPAR) agonists to i) mitigate radiation-induced activation of microglia and astrocytes; ii) prevent radiation-induced alterations of glutamatergic signaling; and iii) inhibit growth of brain metastatic cells, with or without radiation.
- Choudhary M, Naczki C, Chen W, Barlow KD, Case LD, and Metheny-Barlow LJ. Tumor-induced loss of mural Connexin 43 gap junction activity promotes endothelial proliferation. BMC Cancer. 2015 May 23;15(1):427.
- Moore ED, Kooshki M, Wheeler KT, Metheny-Barlow LJ, Robbins ME [deceased]. Differential expression of Homer1a in the hippocampus and cortex likely plays a role in radiation-induced brain injury. Radiat Res. 2014;181(1):21-32.
- Greene-Schloesser D, Payne V, Peiffer A, Hsu F-C, Riddle DR, Zhao W, Chan MD, Metheny-Barlow L. and Robbins ME. The peroxisomal proliferator-activated receptor (PPAR) α agonist, fenofibrate, prevents fractionated whole-brain irradiation-induced cognitive impairment. Radiat Res., 2014;181(1):33-44.
- Moore ED, Kooshki M, Metheny-Barlow LJ, Gallagher PE, Robbins ME [deceased]. Angiotensin-(1-7) prevents radiation-induced inflammation in rat primary astrocytes through regulation of MAP kinase signaling. Free Radic Biol Med. 2013;65():1060-1068.
- Barlow KD, Sanders AM, Soker S, Ergun S, Metheny-Barlow LJ. Pericytes on the tumor vasculature: Jekyll or Hyde?. Cancer Microenviron. 2013;6(1):1-17.
- Vincent A, Lesser G, Brown D, Vern-Gross T, Metheny-Barlow L, Lawrence J, Chan M. Prolonged regression of metastatic leptomeningeal breast cancer that has failed conventional therapy: a case report and review of the literature. J Breast Cancer. 2013;16(1):122-126.
- Buchanan CF, Szot CS, Wilson TD, Akman S, Metheny-Barlow LJ, Robertson JL, Freeman JW, Rylander MN. Cross-talk between endothelial and breast cancer cells regulates reciprocal expression of angiogenic factors in vitro. J Cell Biochem. 2012;113(4):1142-1151.
- Arter AA, Metheny-Barlow L, Gallagher PE, Tallant EA. Angiotensin-(1-7) inhibits proliferative and fibrotic signaling mechanisms in triple negative breast cancer [abstract]. In: Proceedings of the 103rd Annual Meeting of the Amerian Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, Illinois. Philadelphia (PA): AACR. 2012;():Abstr 5224.
- Vern-Gross TZ, Lawrence JA, Case LD, McMullen KP, Bourland JD, Metheny-Barlow LJ, Ellis TL [deceased], Tatter SB, Shaw EG, Urbanic JJ, Chan MD. Breast cancer subtype affects patterns of failure of brain metastases after treatment with stereotactic radiosurgery. J Neurooncol. 2012;110(3):381-388.
- Cook KL, Metheny-Barlow LJ, Tallant EA, Gallagher PE. Angiotensin-(1-7) reduces fibrosis in orthotopic breast tumors. Cancer Res. 2010;70(21):8319-8328.
Cancer/oncogenesis, cell growth, differentiation,d.