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Edna Cukierman, PhD

Edna Cukierman, PhD
About

Associate Professor

Co-leader, Pancreas Research Interest Group

Chair, Institutional Biosafety Committee

Research Program

3D-adhesions formed within in vivo-like fibroblast-derived extracellular matrix
Normal fibroblast-derived 3D culture
Normal fibroblast-derived 3D culture
Primed fibroblast-derived 3D culture
Primed fibroblast-derived 3D culture
Tumor-associated fibroblast-derived 3D culture
Tumor-associated fibroblast-derived 3D culture
Normal fibroblasts on 2D or within normal, primed or tumor-associated 3D ECMs
DIC and immunofluorescence; during ECM production
Tracks of invasive cells moving through control or tumor-associated ECMs
Same cell different substrates; 2D vs. 3D adhesion structures
Model illustrating production of murine fibroblast-derived 3D matrices
Staged in vivo-like 3D stromal matrices; fibronectin (green) and collagen (red)
Tumor microenvironment (desmoplasia)
Human fibroblast within in vivo-like ECM
Simultaneous Multi-Channel Immunofluorescence Analysis (SMIA)
Cukierman lab staff, 2015
A New 3D Model System Developed to Mimic Mechanical Aspects of Pancreatic Cancer

Researchers recently presented a new multidisciplinary approach using a 3D human tissue mimetic model to study how human pancreatic fibrous extracellular matrices (ECMs) interact with pancreatic cancer cells displaying common pancreatic cancer mutations, such as lack of p53 and constitutively active KRAS. Full article at Fox Chase Now

Education, Training & Credentials

Educational Background

  • Postdoctoral Fellow, Craniofacial Developmental Biology and Regeneration Branch (Mentor- Dr. Kenneth M. Yamada), NIH/National Institute of Dental and Craniofacial Research, 1997-2002
  • PhD, Molecular and Cell Biology, Technion-Israel Institute of Technology, 1997
  • MS, Biochemistry, Technion-Israel Institute of Technology, 1993
  • BS, Biology, Technion-Israel Institute of Technology, 1991

Honors & Awards

  • Distinguished Achievement Award in Cancer Research and Clinical Management –Focus in Pancreas- by the Chinese Society of Clinical Oncology (Chinese’s ASCO), 2016
  • DOD Idea Award with Special Focus in Pancreatic Cancer , 2015-2017
  • Image featured at Dulles and PLH Airports (“Life Magnified” by NIH/ASCB), 2014
  • Member of NIH/NCI’s Tumor Progression and Metastasis Study Section, 2013-2019
  • Temple-FCCC Nodal Award, 2013-2015
  • AACR Career Development Award (continuation from 2004), 2006-2007
  • Olympus BioScapes Digital Imaging Competition (Honorable Mention Award), 2006
  • W.W. Smith Charitable Trust Award, 2005-2008
  • Nikon Small World Competition (Image Distinction Award), 2005
  • AACR Career Development Award, 2004-2006
  • National Pancreas Foundation Award, 2004-2005
  • Fellows Award for Research Excellence at the NIH, 2002
Research Profile

Research Program

Research Interests

Desmoplastic Tumor Microenvironment

  • Mechanisms of fibrous desmoplastic activation and maintenance via integrin signaling and cytoskeletal dynamics
  • Pancreatic, renal, mammary gland and other transformative alterations regulated by cancer- or tumor-associated fibroblasts (CAFs or TAFs) and their self-derived extracellular matrices (ECMs)
  • Clinical implications, translational aspects and means of microenvironment activation assessments; compartmental —tumoral and stromal— biomarker detection using multi-spectral and batch digital imaging analyses
  • Decoupling of biochemical and biomechanical influences of desmoplasia by combinational 3D models of cell-derived ECMs and biomimetic material engineering

Lab Overview

Central premise: We postulate that it is possible to reprogram the desmoplastic microenvironment back to its tumor suppressive state and that by doing so one could introduce new means of tumor stalling. This idea is based on the fact that desmoplasia is reminiscent of chronic wound healing pathologies, such as chronic inflammation associated with fibrosis. Two major research efforts in the lab actively test this hypothesis from a tumor microenvironment perspective.

  1. How can we alter desmoplastic activity?

    We have previously demonstrated that desmoplastic extracellular matrices (ECMs) effectively induce an active myofibroblastic phenotype upon naive fibroblastic cells (Amatangelo et al 2005 - http://www.ncbi.nlm.nih.gov/pubmed/16049333). Using syngeneic human fibroblasts harvested from pancreatic or renal cancer patient-matched normal and tumor surgical samples, we prompt cells to produce a human mimetic 3D stroma system. Due to the nature of the 3D system we are poised to dissect mechanisms of desmoplastic fibrillogenesis from mechanisms of desmoplastic ECM-regulated fibroblastic activation. Signaling mechanisms queried in this project include TGFbeta regulation of desmoplastic ECM production as well as ECM controlled integrin signaling, discrete receptor recycling and cytoskeletal reorganization influenced by actin binding proteins such as stromal palladin and alpha-smooth muscle actin. Approaches include the use of specific inhibitor and activator drugs as well as genetic manipulations. Pathophysiological validations are conducted via simultaneous multi-channel immunofluorescence labeling of the original surgical tissue samples. This approach distinguishes tumoral from stromal compartments and uncovers the localization and levels of proteins representative of the above-mentioned signaling pathways and of altered desmoplastic 3D-adhesion structures. To establish clinical relevance, the same approach is combined with clinically annotated human tissue microarrays and with specially developed software, SMIA-CUKIE. This software is implemented as a batch analysis tool that renders spread sheets of quantitative data and images representative of mask area locations and their corresponding markers. We posit that desmoplastic mechanisms of activation not only comprise clinically important occurrences and are patient outcome-predictive but also constitute novel “desmoplastic index” biomarkers. We aim to identify possible new therapeutics that could redirect the stroma.

  2. How does desmoplasia affect tumor development and progression?

Previous efforts by this and other groups have suggested that cancers are full organ (or full body) diseases and that in order to study them one should account for microenvironmental cues and question their effects upon cancer cell behaviors and drugs responses. Hence, we study tumorigenic activities during tumor development and progression in the context of desmoplastic ECMs. Specifically, we seek to define how 3D ECMs, produced by early- versus late-stage fibroblastic cells (i.e., CAFs also known as TAFs), condition tumor cell signaling to affect cancer cell growth, survival, invasion and resistance to drugs. Models independently researched in the lab include pancreatic adenocarcinoma and renal cell carcinoma while stroma regulated breast and lung cancers are studied as part of ongoing collaborative efforts with other groups.

We combine the use of the above mentioned 3D culturing system with mixtures of fibroblastic and cancer cells (at various tumor progression stages) together with other host cells such as tumor altered immune cells and nerve infiltrates. The project conveys analyses that incorporate biochemical, molecular and cell biology approaches with laser scanning confocal, multi-spectra and real time microscopies. Effects of physical cues, such as desmoplastic ECM alignment and stiffness, constitute central aspects of the study. For this, 3D culturing mimicry is accomplished using combinations of patient harvested and biocompatible materials implementing bioengineering and specially designed tissue patterning approaches. Translational efforts and pathophysiological relevancies are investigated, in collaboration with other groups at FCCC, using the same human tumor tissue samples implanted into immune compromised mice (PDX models) as well as via genetic animal models. In addition the study uses formalin-fixed and paraffin-embedded (FFPE) human patient and animal tissue samples to implement a multi-spectra immunofluorescence analysis (SMIA-CUKIE) as above.

This project’s ultimate goal is to better understand the underlying tumor-stromal interactive processes governing tumorigenic behaviors, such as metastasis, in order to identify possible new therapeutics aimed at interfering with these types of tumor-stroma interactions.

Resources
 
  • Quantitative SMIA-CUKIE software outputs representative of assorted stromal marker expression and localization values as well as patient outcomes
    Analyses were conducted in tissue microarrays corresponding to Fox Chase Cancer Center’s PDAC and RCC patient cohorts collected and followed from 1991 to 2012. Data was used in Franco-Barraza, et al; 2016.
    Download the spreadsheet for review. [XLS, 159KB]
  • Simultaneous Multichannel Immunofluorescense Digital Imaging Analyzer
    Software for multi-spectra analysis (SMIA-CUKIE)
    github.com/cukie/SMIA-CUKIE

People

Jennifer Alexander

PhD Candidate

215-214-4219

Janusz Franco-Barraza, MD, PhD

Postdoctoral Associate

Room: W428
215-214-4219

Ruchi Malik, PhD

Postdoctoral Associate

Room: W428
215-214-4219

Tiffany Luong, BS

Scientific Technician I

Room: W428
215-214-4219

Neelima Shah

Microscopy Specialist

Room: W428
215-214-4219

Raj Madhani

Undergraduate Student Assistant

Room: W427
215-214-4219

Ellen Ragan

Administrative Assistant

Room: W16
215-728-4304

Ralph Francescone, PhD

Postdoctoral Researcher

Dustin Rollins

MSc Candidate

Additional Staff

Ashish Abraham, Student Volunteer, Central High School

Jerry So, Student Volunteer

Former Personnel
Michael Amatangelo Kelci R. Holman Jeffrey Simons
Daniel Bassi David Khan Matthildi Valianou
Dorothy Beacham Melissa Lech Fernanda Villamar
Kimberly Brown Roderick Quiros Olga Villamar
Remedios Castelló-Cros Poornima Rao Gary Wilk
Gil Cukierman Mastan Rao Chintalapudi Galia Wilk
James Flaherty Rebecca Roth Stephanie Wirtshafter
Sarah Goldston Brad Rybinski Alexander Zenin
Vivekanad Gupta Corinne Watson Daniel Zinshteyn
 
Extramural Affiliations
Publications

Selected Publications

Malik, R., Lelkes, P.I., Cukierman, E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends in Biotech, 33(4):230-236, 2015. PMCID: PMC4380578 [PubMed]

Rybinski, B., Franco-Barraza, J., and Cukierman, E. The wound healing, chronic fibrosis and cancer progression triad, Physiological Genomics, 46(7):223-244, 2014. PMCID: PMC4035661 [PubMed]

 

Håkanson M, Kobel S, Lutolf MP, Textor M, Cukierman E*, Charnley M*. Controlled Breast Cancer Microarrays for the Deconvolution of Cellular Multilayering and Density Effects upon Drug Responses. PLoS ONE 2012;7(6): e40141. doi:10.1371/journal.pone.0040141 (*co-corresponding author). PLoS ONE [PubMed]

Gupta V, Bassi DE, Simons JD, Devarajan K, Al-Saleem T, Uzzo RG, Cukierman E. Elevated expression of stromal palladin predicts poor clinical outcome in renal cell carcinoma. PLoS One. 2011;6(6):e21494. Epub 2011 Jun 28. PubMed

Goetz JG, Minguet S, Navarro-Lérida I, Lazcano JJ, Samaniego R, Calvo E, Tello M, Osteso-Ibáñez T, Pellinen T, Echarri A, Cerezo A, Klein-Szanto AJ, Garcia R, Keely PJ, Sánchez-Mateos P, Cukierman E, Del Pozo MA. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011 Jul 8;146(1):148-63. PubMed

Lee HO, Mullins SR, Franco-Barraza J, Valianou M, Cukierman E*, Cheng JD*. FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer. 2011 Jun 13;11(1):245. (* co-corresponding author). PubMed

Kwon Y, Cukierman E*, Godwin AK*. Differential expressions of adhesive molecules and proteases define mechanisms of ovarian tumor cell matrix penetration/invasion. PLoS One. 2011 Apr 19;6(4):e18872. (* co-corresponding author). PubMed

Castelló-Cros R, Khan DR, Simons J, Valianou M, Cukierman E. Staged stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and beta1-integrins. BMC Cancer. 2009 Mar 26;9:94. PubMed

Serebriiskii I, Castello-Cros R, Lamb A, Golemis EA, and Cukierman E. Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells. Matrix Biology. 2008;27:573-585. PubMed

Quiros, RM., Valianou, M., Kwon, Y., Brown, KM., Godwin, AK., and Cukierman, E. Ovarian normal and tumor-associated fibroblasts retain in vivo stromal characteristics in a 3-D matrix-dependent manner. Gynecologic Oncology., 110:99-109, 2008. PMCID: PMC2612536 [PubMed]

Yamada, K. M., Cukierman, E. Modeling tissue morphogenesis and cancer in 3D. Cell. 130:601-610, 2007. (Accepted prior to April 2007). [PubMed]

Amatangelo MD, Bassi DE, Klein-Szanto AJ, Cukierman E. Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. Am J Pathol. 2005;167(2):475-88. PubMed

Cukierman E, Pankov R, Stevens DR, and Yamada KM. Taking cell-matrix adhesions to the third dimension. Science. 2001;294:1708-1712. PubMed

Additional Publications

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