Publications by authors named "Nastaran Zahir"

11 Publications

  • Page 1 of 1

Developing and validating model systems for immuno-oncology.

Cancer Cell 2021 08 10;39(8):1018-1022. Epub 2021 Jun 10.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. Electronic address:

Owing to clinical success of immune-checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno-oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno-oncology modeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.05.017DOI Listing
August 2021

The NCI Cancer Tissue Engineering Collaborative Research Program is a highly interdisciplinary and focused community.

iScience 2021 May 30;24(5):102441. Epub 2021 Apr 30.

Division of Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111673PMC
May 2021

Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.

J Exp Med 2021 05;218(5)

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA.

Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20191360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025243PMC
May 2021

Education and Outreach in Physical Sciences in Oncology.

Trends Cancer 2021 01 7;7(1):3-9. Epub 2020 Nov 7.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL, USA; Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA; Center for Immunotherapeutic Transport Oncophysics, Houston Methodist Research Institute, Houston, TX, USA. Electronic address:

Physical sciences are often overlooked in the field of cancer research. The Physical Sciences in Oncology Initiative was launched to integrate physics, mathematics, chemistry, and engineering with cancer research and clinical oncology through education, outreach, and collaboration. Here, we provide a framework for education and outreach in emerging transdisciplinary fields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895467PMC
January 2021

Characterizing the ecological and evolutionary dynamics of cancer.

Nat Genet 2020 08 27;52(8):759-767. Epub 2020 Jul 27.

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

Tumor initiation and progression are somatic evolutionary processes driven by the accumulation of genetic alterations, some of which confer selective fitness advantages to the host cell. This gene-centric model has shaped the field of cancer biology and advanced understanding of cancer pathophysiology. Importantly, however, each genotype encodes diverse phenotypic traits that permit acclimation to varied microenvironmental conditions. Epigenetic and transcriptional changes also contribute to the heritable phenotypic variation required for evolution. Additionally, interactions between cancer cells and surrounding stromal and immune cells through autonomous and non-autonomous signaling can influence competition for survival. Therefore, a mechanistic understanding of tumor progression must account for evolutionary and ecological dynamics. In this Perspective, we outline technological advances and model systems to characterize tumor progression through space and time. We discuss the importance of unifying experimentation with computational modeling and opportunities to inform cancer control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-0668-4DOI Listing
August 2020

The National Cancer Institute Investment in Biomechanics in Oncology Research.

Adv Exp Med Biol 2018;1092:1-10

Division of Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

The qualitative description of tumors feeling stiffer than surrounding normal tissue has been long appreciated in the clinical setting. These empirical observations have been corroborated by the precise measurement and characterization of mechanical properties of cancerous tissues. Much of the advancement in our understanding of mechanics in oncology has been enabled by the development of innovative technologies designed to probe cells and tissues as well as integrative software analysis tools that facilitate biological interpretation and generation of testable hypotheses. While some mechanics in oncology research has been investigator-initiated and supported by the National Cancer Institute (NCI), several NCI programs described herein have helped to foster the growth of the burgeoning field. Programs highlighted in this chapter include Innovative Molecular Analysis Technologies (IMAT), Physical Sciences-Oncology Network (PS-ON), Tumor Microenvironment Network (TMEN), Integrative Cancer Biology Program (ICBP), and the Cancer Systems Biology Consortium (CSBC). This chapter showcases the scientific contributions of these programs to the field of biomechanics in oncology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-319-95294-9_1DOI Listing
July 2019

The NCI Physical Sciences - Oncology Network.

Authors:
Nastaran Zahir

Trends Cancer 2018 04 7;4(4):e1-e6. Epub 2018 Apr 7.

Nastaran Zahir is Associate Director of the Physical Sciences - Oncology Network in the Division of Cancer Biology at the National Cancer Institute. Dr. Zahir coordinates cross-cutting efforts to integrate physical sciences perspectives with cancer research by fostering transdisciplinary research collaborations, supporting education and outreach programs, and promoting resources for data sharing and biospecimen standards.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2018.03.008DOI Listing
April 2018

Tensional homeostasis and the malignant phenotype.

Cancer Cell 2005 Sep;8(3):241-54

Department of Bioengineering, University of Pennsylvania, Philadelphia, 19104, USA.

Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccr.2005.08.010DOI Listing
September 2005

Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion.

Cell Motil Cytoskeleton 2005 Jan;60(1):24-34

Institute for Medicine and Engineering, University of Pennsylvania, PA 19104, USA.

The morphology and cytoskeletal structure of fibroblasts, endothelial cells, and neutrophils are documented for cells cultured on surfaces with stiffness ranging from 2 to 55,000 Pa that have been laminated with fibronectin or collagen as adhesive ligand. When grown in sparse culture with no cell-cell contacts, fibroblasts and endothelial cells show an abrupt change in spread area that occurs at a stiffness range around 3,000 Pa. No actin stress fibers are seen in fibroblasts on soft surfaces, and the appearance of stress fibers is abrupt and complete at a stiffness range coincident with that at which they spread. Upregulation of alpha5 integrin also occurs in the same stiffness range, but exogenous expression of alpha5 integrin is not sufficient to cause cell spreading on soft surfaces. Neutrophils, in contrast, show no dependence of either resting shape or ability to spread after activation when cultured on surfaces as soft as 2 Pa compared to glass. The shape and cytoskeletal differences evident in single cells on soft compared to hard substrates are eliminated when fibroblasts or endothelial cells make cell-cell contact. These results support the hypothesis that mechanical factors impact different cell types in fundamentally different ways, and can trigger specific changes similar to those stimulated by soluble ligands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cm.20041DOI Listing
January 2005

Death in the third dimension: apoptosis regulation and tissue architecture.

Curr Opin Genet Dev 2004 Feb;14(1):71-80

Department of Bioengineering and Institute for Medicine and Engineering, 1170 Vagelos Research Laboratory, 3340 Smith Walk, Philadelphia, PA 19104-6383, USA.

Tissue development, homeostasis and tumor pathogenesis all depend upon a complex dialogue between multiple cell types operating within a dynamic three-dimensional (3D) tissue extracellular matrix microenvironment. A major issue is whether the spatial organization of a cell within this 3D tissue microenvironment could modulate cell responsiveness to regulate cell fate decisions such as survival, and if so how. Classic developmental model systems and transgenic animals are instructive but pose special challenges for investigators conducting signaling studies and biochemical assays in tissues. As an alternative, 3D culture model systems exist in which cell-adhesion dependent tissue architecture, heterotypic cell-cell interactions and tissue differentiation can be recapitulated with good fidelity. 3D cell culture models are slowly revealing how tissue architecture can dramatically influence how a cell responds to exogenous stimuli to modify its apoptotic behavior and hence should prove instrumental for identifying novel cell death pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gde.2003.12.005DOI Listing
February 2004

Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

J Cell Biol 2003 Dec;163(6):1397-407

Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.200302023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173718PMC
December 2003
-->