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Edna Cukierman, PhD

Edna Cukierman, PhD
About

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 and Training

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

  • American Gastroenterological Association (AGA) Inducted Fellow, 2020
  • American Society of Mattrix bilogy (ASMB) Elected Council Member, 2020-2023
  • Worldwide Cancer Research Foundation Award, 2020-2021
  • American Society of Matrix Biology (ASMB) Image Award (dual honor), 2019-2020
  • 5th District AHEPA Cancer Research Foundation, Inc. 2019 Award, 2019-2020
  • 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
 
  • Simultaneous Multichannel Immunofluorescence Digital Imaging Analyzer
    Software for multi-spectra analysis (SMIA-CUKIE)
    github.com/cukie/SMIA-CUKIE
  • 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 Fanco-Barraza, et al., 2017. 

Download the spreadsheet for review. [XLS, 151KB]

Former Personnel

Ashish Abraham
Jennifer Alexander
Michael Amatangelo
Daniel Bassi
Dorothy Beacham
Kimberly Brown
Remedios Castelló-Cros
Lauren Cheifitz
Gil Cukierman
Jonte Desire
Xiaoshen Dong
Stephanie Elbe
James Flaherty
Sarah Goldston
Vivekanad Gupta
Kelci R. Holman
David Khan
Melissa Lech
Raj Madhani
Ruchi Malik
Roderick Quiros
Ellen Ragan
Poornima Rao
Mastan Rao Chintalapudi
Rebecca Roth
Dustin Rollins
Brad Rybinski
Jeffery Simons
Jerry So
Julie Sosa
Matthildi Valianou
Fernanda Villamar
Olga Villamar
Corinne Watson
Gary Wilk
Galia Wilk
Stephanie Wirtshafter
Alexander Zeni

 
Extramural Affiliations
Lab Staff

Ralph Francescone, PhD

Postdoctoral Researcher

Janusz Franco-Barraza, MD, PhD

Postdoctoral Associate

Room: W428
215-214-4219

Charline Ogier PhD

M&C Greenberg Pancreatic Cancer Institute Postoctoral Fellow

Room: W446
215-214-3742

Kristopher Raghavan

PhD Candidate

215-214-4219

Tiffany Luong, BS

Scientific Technician I

Room: W428
215-214-4219

Debora B Vendramini Costa, PhD

Postdoctoral Associate

Room: W428
215-214-4219

Jaye Gardiner, PhD

Postdoctoral Fellow Researcher

Room: W428
215 214-4219
Publications

Selected Publications

Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, Hynes RO, Jain RK, Janowitz T, Jorgensen C, Kimmelman AC, Kolonin MG, Maki RG, Powers RS, Pure E, Ramirez DC, Scherz-Shouval R, Sherman MH, Stewart S, Tlsty TD, Tuveson DA, Watt FM, Weaver V, Weeraratna AT, Werb Z: A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 2020 https://doi.org/10.1038/s41568-019-0238-1

Franco-Barraza J, Raghavan KS, Luong T, Cukierman E: Engineering clinically-relevant human fibroblastic cell-derived extracellular matrices. Cell-derived Matrices. Methods in Cell Biology: Elsevier, 2020. https://doi.org/10.1016/bs.mcb.2019.11.014

Zeltz C, Alam J, Liu H, Erusappan PM, Hoschuetzky H, Molven A, Parajuli H, Cukierman E, Costea D-E, Lu N, Gullberg D: α11β1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration. Cancers 2019, 11:765. https://doi.org/10.3390/cancers11060765

Malik R, Luong T, Cao X, Han B, Shah N, Franco-Barraza J, Han L, Shenoy VB, Lelkes PI, Cukierman E: Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2. Matrix Biol 2019, 81:50-69. PMC6504628

Gardiner JC, Raghavan KS, Alexander JI, Franco-Barraza J, Cukierman E: Fibroblastic Cell-derived Extracellular Matrices: A Cell Culturing System to Model Key Aspects of the Tumor Microenvironment. Decellularized Extracellular Matrix: Characterization, Fabrication and Applications: The Royal Society of Chemistry 2020, 2019. pp. 305-27. (Book Chapter)

Kaur A, Ecker BL, Douglass SM, Kugel CH, 3rd, Webster MR, Almeida FV, Somasundaram R, Hayden J, Ban E, Ahmadzadeh H, Franco-Barraza J, Shah N, Mellis IA, Keeney F, Kossenkov A, Tang HY, Yin X, Liu Q, Xu X, Fane M, Brafford P, Herlyn M, Speicher DW, Wargo JA, Tetzlaff MT, Haydu LE, Raj A, Shenoy V, Cukierman E, Weeraratna AT: Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov 2019, 9:64-81. PMC6328333

Jones CE, Hammer AM, Cho Y, Sizemore GM, Cukierman E, Yee LD, Ghadiali SN, Ostrowski MC, Leight JL: Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland. Neoplasia 2019, 21:132-45. PMC6293034

Francescone R, Barbosa Vendramini-Costa D, Franco-Barraza J, Wagner J, Muir A, Lau AN, Gabitova L, Pazina T, Gupta S, Luong T, Shah N, Rollins D, Malik R, Thapa R, Restifo D, Zhou Y, Cai KQ, Hensley HH, Tan Y, Kruger WD, Devarajan K, Balachandran S, Klein-Szanto AJ, El-Deiry WS, Vander Heiden MG, Peri S, Campbell KS, Astsaturov I, Cukierman E: NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional supply and immunosuppression. bioRxiv 2019. https://doi.org/10.1101/330209

Gabitova L, Peri S, Restifo D, Klochkova A, Hartman TR, O'Reilly AM, Francescone R, Franco-Barraza J, Shah N, Nicolas E, Handorf EA, Cai KQ, Mazitova A, Sloma I, Chiaverelli R, Moffitt R, Golemis EA, Cukierman E, Astsaturov I: Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer. bioRxiv 2019:633719. http://dx.doi.org/10.1101/633719

Padhi A, Singh K, Franco-Barraza J, Marston D, Hahn KM, Cukierman E, Kapania R, Nain AS: Nano-twines to twine-bridges: Role of force exerting perpendicular lateral protrusions in fibroblastic cell contraction. bioRxiv 2019:711507.  https://doi.org/10.1101/711507

Fragoso MF, Romualdo GR, Vanderveer LA, Franco-Barraza J, Cukierman E, Clapper ML, Carvalho RF, Barbisan LF: Lyophilized açaí pulp (Euterpe oleracea Mart) attenuates colitis-associated colon carcinogenesis while its main anthocyanin has the potential to affect the motility of colon cancer cells. Food and Chemical Toxicology 2018, 121:237-45. PubMed

Shafi, A.A., Schiewer, M.J., de Leeuw, R., Dylgjeri, E., McCue, P.A., Shah, N., Gomella, L.G., Lallas, C.D., Trabulsi, E.J., Centenera, M.M., Hickey, T.E., Butler, L.M., Raj, G.V., Tilley, W.D.,Cukierman, E., Knudsen, K.E.  Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response.  European Urology Oncology 2018 (in press). DOI

Franco-Barraza J, Francescone R, Luong T, Shah N, Madhani R, Cukierman G, Dulaimi E, Devarajan K, Egleston BL, Nicolas E, Alpaugh KR, Malik R, Uzzo RG, Hoffman JP, Golemis EA, Cukierman E: Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence. eLife 2017 http://dx.doi.org/10.7554/eLife.20600

Roy I, Boyle KA, Vonderhaar EP, Zimmerman NP, Gorse E, Mackinnon AC, Hwang RF, Franco-Barraza J, Cukierman E, Tsai S, Evans DB, Dwinell MB: Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma. Laboratory Investigation 2017. PubMed

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