Publications by authors named "Edna Cukierman"

67 Publications

Meaningful connections: Interrogating the role of physical fibroblast cell-cell communication in cancer.

Adv Cancer Res 2022 24;154:141-168. Epub 2022 Feb 24.

Cancer Signaling and Epigenetics Program, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United States. Electronic address:

As part of the connective tissue, activated fibroblasts play an important role in development and disease pathogenesis, while quiescent resident fibroblasts are responsible for sustaining tissue homeostasis. Fibroblastic activation is particularly evident in the tumor microenvironment where fibroblasts transition into tumor-supporting cancer-associated fibroblasts (CAFs), with some CAFs maintaining tumor-suppressive functions. While the tumor-supporting features of CAFs and their fibroblast-like precursors predominantly function through paracrine chemical communication (e.g., secretion of cytokine, chemokine, and more), the direct cell-cell communication that occurs between fibroblasts and other cells, and the effect that the remodeled CAF-generated interstitial extracellular matrix has in these types of cellular communications, remain poorly understood. Here, we explore the reported roles fibroblastic cell-cell communication play within the cancer stroma context and highlight insights we can gain from other disciplines.
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http://dx.doi.org/10.1016/bs.acr.2022.01.004DOI Listing
February 2022

Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma.

Nat Commun 2022 03 16;13(1):1381. Epub 2022 Mar 16.

Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.
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http://dx.doi.org/10.1038/s41467-022-28801-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927161PMC
March 2022

The Few yet Fabulous Pancreatic Stellate Cells Give Rise to Protumoral CAFs.

Authors:
Edna Cukierman

Cancer Discov 2022 02;12(2):296-298

Cancer Signaling and Epigenetics Program, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania.

Cancer-associated fibroblast (CAF) pro- and anti-pancreatic cancer functional dichotomy has been at the center of numerous studies. In this issue of , Helms and colleagues demonstrate that although pancreatic stellate cell-derived CAFs constitute a desmoplastic cell minority, these cells play a protumorigenic role via microenvironmental mechanomodulation..
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http://dx.doi.org/10.1158/2159-8290.CD-21-1501DOI Listing
February 2022

A Reflection on How Carcinoma-Associated Fibroblasts Were Recognized as Active Participants of Epithelial Tumorigenesis.

Authors:
Edna Cukierman

Cancer Res 2021 09;81(18):4668-4670

Cancer Signaling and Epigenetics, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.

Today's view of cancer as a systemic disease was facilitated by studies accentuating the local as well as the systemic role that non-tumorigenic cells, such as carcinoma-associated fibroblasts, play in cancer onset, development, and progression. The study highlighted in this Landmark was instrumental for supporting the idea that cancer is a full-body disease that depends on reciprocal interactions between cancer cells and the tumor microenvironment. Fibroblasts are mesenchymal cells of the connective tissue and are responsible for maintaining tissue homeostasis. Importantly, contractile myofibroblastic activation and immunoregulatory fibroblastic nemosis (the process of mesenchymal cell activation, followed by death, associated with release of proinflammatory molecules) constitute two functional aspects of fibroblasts that are essential for organogenesis as well as for modulating wound healing. Yet, in epithelial cancers, fibroblastic cell functions are chronically misregulated. The study by Olumi and colleagues published in in 1999 exemplifies how normal fibroblasts play a tumor-suppressive role and how modulating fibroblastic activity provides carcinoma-associated fibroblasts with tumor-promoting functions, similar to the needed "second hit" in a tumor suppressor gene. The emphasis on tumor/fibroblast interactions has provided a new framework for thinking about tumorigenesis as well as new targets for therapeutic intervention..
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2553DOI Listing
September 2021

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression.

Cancer Discov 2021 02 30;11(2):446-479. Epub 2020 Oct 30.

Cancer Biology Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1 cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1 CAFs are intrinsically immunosuppressive and inhibit natural killer cell-mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858242PMC
February 2021

Deconstructing tumor heterogeneity: the stromal perspective.

Oncotarget 2020 Oct 6;11(40):3621-3632. Epub 2020 Oct 6.

Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA.

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field.
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http://dx.doi.org/10.18632/oncotarget.27736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546755PMC
October 2020

Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.

Cancer Cell 2020 10 24;38(4):567-583.e11. Epub 2020 Sep 24.

Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA; The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Kazan Federal University, Kazan, Russian Federation. Electronic address:

Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.
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http://dx.doi.org/10.1016/j.ccell.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572882PMC
October 2020

Author Correction: Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction.

Commun Biol 2020 Aug 21;3(1):470. Epub 2020 Aug 21.

Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s42003-020-01196-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442792PMC
August 2020

Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours.

Nat Metab 2020 08 6;2(8):775-792. Epub 2020 Jul 6.

Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.

Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-β-SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.
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http://dx.doi.org/10.1038/s42255-020-0226-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438275PMC
August 2020

Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction.

Commun Biol 2020 07 21;3(1):390. Epub 2020 Jul 21.

Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, USA.

Aligned extracellular matrix fibers enable fibroblasts to undergo myofibroblastic activation and achieve elongated shapes. Activated fibroblasts are able to contract, perpetuating the alignment of these fibers. This poorly understood feedback process is critical in chronic fibrosis conditions, including cancer. Here, using fiber networks that serve as force sensors, we identify "3D perpendicular lateral protrusions" (3D-PLPs) that evolve from lateral cell extensions named twines. Twines originate from stratification of cyclic-actin waves traversing the cell and swing freely in 3D to engage neighboring fibers. Once engaged, a lamellum forms and extends multiple secondary twines, which fill in to form a sheet-like PLP, in a force-entailing process that transitions focal adhesions to activated (i.e., pathological) 3D-adhesions. The specific morphology of PLPs enables cells to increase contractility and force on parallel fibers. Controlling geometry of extracellular networks confirms that anisotropic fibrous environments support 3D-PLP formation and function, suggesting an explanation for cancer-associated desmoplastic expansion.
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http://dx.doi.org/10.1038/s42003-020-01117-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374753PMC
July 2020

CD38 in cancer-associated fibroblasts promotes pro-tumoral activity.

Lab Invest 2020 12 1;100(12):1517-1531. Epub 2020 Jul 1.

Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel.

Primary and metastatic melanoma progression are supported by a local microenvironment comprising, inter alia, of cancer-associated fibroblasts (CAFs). We previously reported in orthotropic/syngeneic mouse models that the stromal ectoenzyme CD38 participates in melanoma growth and metastasis. The results presented here suggest that CD38 is a novel regulator of CAFs' pro-tumorigenic functions. Orthotopic co-implantation of CD38 deficient fibroblasts and B16F10 melanoma cells limited tumor size, compared with CD38-expressing fibroblasts. Intrinsically, CAF-CD38 promoted migration of primary fibroblasts toward melanoma cells. Further, in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL-12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factors that promote cell invasion, migration, and angiogenesis.
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http://dx.doi.org/10.1038/s41374-020-0458-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686132PMC
December 2020

Sustained hedgehog signaling in medulloblastoma tumoroids is attributed to stromal astrocytes and astrocyte-derived extracellular matrix.

Lab Invest 2020 09 26;100(9):1208-1222. Epub 2020 May 26.

Cancer biology program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.

Aberrant activation of the hedgehog (Hh) signaling pathway is associated with the formation of medulloblastoma (MB), the most common malignant pediatric brain tumor. However, tumor cells from human and mouse MB can not be passaged or preserved after being adherently cultured. Moreover, Hh signaling in MB cells is inactivated in such culture. Here we demonstrate that MB cells are capable of forming tumoroids (tumor spheroids) in vitro under optimized conditions, which can be further passaged and cryopreserved. More importantly, MB cells maintain Hh pathway activation and cell proliferation in tumoroids. Our studies further reveal that tumoroids-forming capacity of MB cells relies on astrocytes, a major component of the MB microenvironment. Astrocytes facilitate the formation of MB tumoroids by secreting sonic hedgehog (Shh) and generating astrocyte-derived extracellular matrix. These findings demonstrate the critical role of stromal astrocytes in supporting the survival and proliferation of MB cells in vitro. This study establishes a valid model for long-term culture of primary MB cells, which could be greatly beneficial for future investigation of MB tumorigenicity and the development of improved approaches to treat MB.
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http://dx.doi.org/10.1038/s41374-020-0443-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442735PMC
September 2020

Cancer associated fibroblast: Mediators of tumorigenesis.

Matrix Biol 2020 09 22;91-92:19-34. Epub 2020 May 22.

Cancer Biology, Fox Chase Cancer Center, Philadelphia PA 19111, United States; Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia PA 19111, United States. Electronic address:

It is well accepted that the tumor microenvironment plays a pivotal role in cancer onset, development, and progression. The majority of clinical interventions are designed to target either cancer or stroma cells. These emphases have been directed by one of two prevailing theories in the field, the Somatic Mutation Theory and the Tissue Organization Field Theory, which represent two seemingly opposing concepts. This review proposes that the two theories are mutually inclusive and should be concurrently considered for cancer treatments. Specifically, this review discusses the dynamic and reciprocal processes between stromal cells and extracellular matrices, using pancreatic cancer as an example, to demonstrate the inclusivity of the theories. Furthermore, this review highlights the functions of cancer associated fibroblasts, which represent the major stromal cell type, as important mediators of the known cancer hallmarks that the two theories attempt to explain.
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http://dx.doi.org/10.1016/j.matbio.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434664PMC
September 2020

Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma.

Am J Pathol 2020 08 24;190(8):1735-1751. Epub 2020 Apr 24.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr) mice were crossed with the Kras; Trp53; Ptf1a (KPC) model of metastatic PDA. Ddr1; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1 mice were crossed with the Kras; Ptf1a neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1 models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1 animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.
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http://dx.doi.org/10.1016/j.ajpath.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416078PMC
August 2020

Engineering clinically-relevant human fibroblastic cell-derived extracellular matrices.

Methods Cell Biol 2020 21;156:109-160. Epub 2020 Jan 21.

Cancer Biology, The Martin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, United States. Electronic address:

Three-dimensional (3D) culturing models, replicating in vivo tissue microenvironments that incorporate native extracellular matrix (ECM), have revolutionized the cell biology field. Fibroblastic cells generate lattices of interstitial ECM proteins. Cell interactions with ECMs and with molecules sequestered/stored within these are crucial for tissue development and homeostasis maintenance. Hence, ECMs provide cells with biochemical and biomechanical cues to support and locally control cell function. Further, dynamic changes in ECMs, and in cell-ECM interactions, partake in growth, development, and temporary occurrences such as acute wound healing. Notably, dysregulation in ECMs and fibroblasts could be important triggers and modulators of pathological events such as developmental defects, and diseases associated with fibrosis and chronic inflammation such as cancer. Studying the type of fibroblastic cells producing these matrices and how alterations to these cells enable changes in ECMs are of paramount importance. This chapter provides a step-by-step method for producing multilayered (e.g., 3D) fibroblastic cell-derived matrices (fCDM). Methods also include means to assess ECM topography and other cellular traits, indicative of fibroblastic functional statuses, like naïve/normal vs. inflammatory and/or myofibroblastic. For these, protocols include indications for isolating normal and diseased fibroblasts (i.e., cancer-associated fibroblasts known as CAFs). Protocols also include means for conducting microscopy assessments, querying whether fibroblasts present with fCDM-dependent normal or CAF phenotypes. These are supported by discrete semi-quantitative digital imaging analyses, providing some imaging processing advice. Additionally, protocols include descriptions for effective fCDM decellularization, which renders cellular debris-free patho/physiological in vivo-like scaffolds, suitable as 3D substrates for subsequent cell culturing.
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http://dx.doi.org/10.1016/bs.mcb.2019.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298733PMC
December 2020

A framework for advancing our understanding of cancer-associated fibroblasts.

Nat Rev Cancer 2020 03 24;20(3):174-186. Epub 2020 Jan 24.

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
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http://dx.doi.org/10.1038/s41568-019-0238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046529PMC
March 2020

α11β1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration.

Cancers (Basel) 2019 Jun 1;11(6). Epub 2019 Jun 1.

Department of Biomedicine and Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, NO-5009 Bergen, Norway.

Integrin α11β1 is a collagen receptor that has been reported to be overexpressed in the stroma of non-small cell lung cancer (NSCLC) and of head and neck squamous cell carcinoma (HNSCC). In the current study, we further analyzed integrin α11 expression in 14 tumor types by screening a tumor tissue array while using mAb 203E3, a newly developed monoclonal antibody to human α11. Different degrees of expression of integrin α11 were observed in the stroma of breast, ovary, skin, lung, uterus, stomach, and pancreatic ductal adenocarcinoma (PDAC) tumors. Co-expression queries with the myofibroblastic cancer-associated fibroblast (myCAF) marker, alpha smooth muscle actin (αSMA), demonstrated a moderate level of α11 in myCAFs associated with PDAC and HNSCC tumors, and a lack of α11 expression in additional stromal cells (i.e., cells positive for fibroblast-specific protein 1 (FSP1) and NG2). The new function-blocking α11 antibody, mAb 203E1, inhibited cell adhesion to collagen I, partially hindered fibroblast-mediated collagen remodeling and obstructed the three-dimensional (3D) migration rates of PDAC myCAFs. Our data demonstrate that integrin α11 is expressed in a subset of non-pericyte-derived CAFs in a range of cancers and suggest that α11β1 constitutes an important receptor for collagen remodeling and CAF migration in the tumor microenvironment (TME).
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http://dx.doi.org/10.3390/cancers11060765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627481PMC
June 2019

Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland.

Neoplasia 2019 01 12;21(1):132-145. Epub 2018 Dec 12.

Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210; The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. Electronic address:

The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.
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http://dx.doi.org/10.1016/j.neo.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293034PMC
January 2019

Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response.

Eur Urol Oncol 2018 Sep 6;1(4):325-337. Epub 2018 Jun 6.

Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

Background: Androgen deprivation therapy is a first-line treatment for disseminated prostate cancer (PCa). However, virtually all tumors become resistant and recur as castration-resistant PCa, which has no durable cure. One major hurdle in the development of more effective therapies is the lack of preclinical models that adequately recapitulate the heterogeneity of PCa, significantly hindering the ability to accurately predict therapeutic response.

Objective: To leverage the ex vivo culture method termed (PDE) to examine the impact of PCa therapeutics on a patient-by-patient basis.

Design Setting And Participants: Fresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response.

Outcome Measurements And Statistical Analysis: The impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices).

Results And Limitations: PDE maintained the integrity of the native tumor microenvironment (TME), tumor tissue morphology, viability, and endogenous hormone signaling. Tumor cells in this model system exhibited de novo proliferative capacity. Examination of the native TME in the PDE revealed a first-in-field insight into patient-specific desmoplastic stromal indices and predicted responsiveness to AR-directed therapeutics.

Conclusions: The PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens tailored to individuals. Discernment of novel stromal markers may provide a basis for applying precision medicine in treating advanced PCa, which would have a transformative effect on patient outcomes.

Patient Summary: In this study, an innovative model system was used to more effectively mimic human disease. The patient-derived explant (PDE) system can be used to predict therapeutic response and identify novel targets in advanced disease. Thus, the PDE will be an asset for the development of novel metrics for the implementation of precision medicine in prostate cancer.The patient-derived explant (PDE) model allows for a comprehensive evaluation of individual human tumors in their native tumor microenvironment (TME). TME analysis revealed first-in-field insight into predicted tumor responsiveness to AR-directed therapeutics through evaluation of patient-specific desmoplastic stromal indices.
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http://dx.doi.org/10.1016/j.euo.2018.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241309PMC
September 2018

Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility.

Cancer Discov 2019 01 2;9(1):64-81. Epub 2018 Oct 2.

The Wistar Institute, Philadelphia, Pennsylvania.

Physical changes in skin are among the most visible signs of aging. We found that young dermal fibroblasts secrete high levels of extracellular matrix (ECM) constituents, including proteoglycans, glycoproteins, and cartilage-linking proteins. The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of melanoma cells. Reconstituting HAPLN1 inhibited metastasis in an aged microenvironment, in 3-D skin reconstruction models, and . Intriguingly, aged fibroblast-derived matrices had the opposite effect on the migration of T cells, inhibiting their motility. HAPLN1 treatment of aged fibroblasts restored motility of mononuclear immune cells, while impeding that of polymorphonuclear immune cells, which in turn affected regulatory T-cell recruitment. These data suggest that although age-related physical changes in the ECM can promote tumor cell motility, they may adversely affect the motility of some immune cells, resulting in an overall change in the immune microenvironment. Understanding the physical changes in aging skin may provide avenues for more effective therapy for older patients with melanoma. SIGNIFICANCE: These data shed light on the mechanochemical interactions that occur between aged skin, tumor, and immune cell populations, which may affect tumor metastasis and immune cell infiltration, with implications for the efficacy of current therapies for melanoma...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328333PMC
January 2019

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 Chem Toxicol 2018 Nov 6;121:237-245. Epub 2018 Sep 6.

Department of Morphology, Institute of Biosciences of Botucatu, UNESP, Botucatu, SP, Brazil. Electronic address:

This study evaluated the possible protective effects of lyophilized açaí pulp (AP) in a colitis-associated carcinogenesis (CAC) rat model and the modifying effect of cyanidin 3-rutinoside (C3R) on the motility of RKO colon adenocarcinoma cells, using the wound healing assay. Male Wistar rats were induced to develop CAC using 1,2-dimethylhydrazine (DMH) and 2,4,6-trinitrobenzene acid (TNBS). Animals were randomly assigned to different groups that received basal diet or basal diet supplemented with 5.0% or 7.5% lyophilized AP. The findings indicate: 1) C3R (25 μM) has the potential to reduce RKO cell motility in vitro; 2) ingestion of lyophilized AP reduces the total number of aberrant crypt foci (ACF), ACF multiplicity, tumor cell proliferation and incidence of tumors with high grade dysplasia; 3) AP increases the gene expression of negative regulators of cell proliferation such as Dlc1 and Akt3, as well as inflammation (Ppara). Thus, lyophilized AP could exert a potential antitumor activity.
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http://dx.doi.org/10.1016/j.fct.2018.08.078DOI Listing
November 2018

Matrix-regulated integrin αβ maintains αβ-dependent desmoplastic traits prognostic of neoplastic recurrence.

Elife 2017 01 31;6. Epub 2017 Jan 31.

Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.

Desmoplasia, a fibrotic mass including cancer-associated fibroblasts (CAFs) and self-sustaining extracellular matrix (D-ECM), is a puzzling feature of pancreatic ductal adenocarcinoma (PDACs). Conflicting studies have identified tumor-restricting and tumor-promoting roles of PDAC-associated desmoplasia, suggesting that individual CAF/D-ECM protein constituents have distinguishable tumorigenic and tumor-repressive functions. Using 3D culture of normal pancreatic versus PDAC-associated human fibroblasts, we identified a CAF/D-ECM phenotype that correlates with improved patient outcomes, and that includes CAFs enriched in plasma membrane-localized, active αβ-integrin. Mechanistically, we established that TGFβ is required for D-ECM production but dispensable for D-ECM-induced naïve fibroblast-to-CAF activation, which depends on αβ-integrin redistribution of pFAK-independent active αβ-integrin to assorted endosomes. Importantly, the development of a simultaneous multi-channel immunofluorescence approach and new algorithms for computational batch-analysis and their application to a human PDAC panel, indicated that stromal localization and levels of active SMAD2/3 and αβ-integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool.
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http://dx.doi.org/10.7554/eLife.20600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283834PMC
January 2017

Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma.

Lab Invest 2017 03 16;97(3):302-317. Epub 2017 Jan 16.

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, USA.

The mechanisms by which the extreme desmoplasia observed in pancreatic tumors develops remain unknown and its role in pancreatic cancer progression is unsettled. Chemokines have a key role in the recruitment of a wide variety of cell types in health and disease. Transcript and protein profile analyses of human and murine cell lines and human tissue specimens revealed a consistent elevation in the receptors CCR10 and CXCR6, as well as their respective ligands CCL28 and CXCL16. Elevated ligand expression was restricted to tumor cells, whereas receptors were in both epithelial and stromal cells. Consistent with its regulation by inflammatory cytokines, CCL28 and CCR10, but not CXCL16 or CXCR6, were upregulated in human pancreatitis tissues. Cytokine stimulation of pancreatic cancer cells increased CCL28 secretion in epithelial tumor cells but not an immortalized activated human pancreatic stellate cell line (HPSC). Stellate cells exhibited dose- and receptor-dependent chemotaxis in response to CCL28. This functional response was not linked to changes in activation status as CCL28 had little impact on alpha smooth muscle actin levels or extracellular matrix deposition or alignment. Co-culture assays revealed CCL28-dependent chemotaxis of HPSC toward cancer but not normal pancreatic epithelial cells, consistent with stromal cells being a functional target for the epithelial-derived chemokine. These data together implicate the chemokine CCL28 in the inflammation-mediated recruitment of cancer-associated stellate cells into the pancreatic cancer parenchyma.
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http://dx.doi.org/10.1038/labinvest.2016.146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334280PMC
March 2017

Preparation of Extracellular Matrices Produced by Cultured and Primary Fibroblasts.

Curr Protoc Cell Biol 2016 06 1;71:10.9.1-10.9.34. Epub 2016 Jun 1.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Fibroblasts secrete and organize extracellular matrix (ECM), which provides structural support for their adhesion, migration, and tissue organization, besides regulating cellular functions such as growth and survival. Cell-to-matrix interactions are vital for vertebrate development. Disorders in these processes have been associated with fibrosis, developmental malformations, cancer, and other diseases. This unit describes a method for preparing a three-dimensional matrix derived from fibroblastic cells; the matrix is three-dimensional, cell and debris free, and attached to a two-dimensional culture surface. Cell adhesion and spreading are normal on these matrices. This matrix can also be compressed into a two-dimensional matrix and solubilized to study the matrix biochemically. © 2016 by John Wiley & Sons, Inc.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058441PMC
http://dx.doi.org/10.1002/cpcb.2DOI Listing
June 2016

Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions.

Curr Opin Cell Biol 2016 10 20;42:80-93. Epub 2016 May 20.

Fox Chase Cancer Center, Cancer Biology, Temple Health, 333 Cottman Ave, Philadelphia, PA 19111, USA. Electronic address:

Stromal dynamic reciprocity (SDR) consists of the biophysical and biochemical interplay between connective tissue elements that regulate and maintain organ homeostasis. In epithelial cancers, chronic alterations of SDR result in the once tumor-restrictive stroma evolving into a 'new' tumor-permissive environment. This altered stroma, known as desmoplasia, is initiated and maintained by cancer associated fibroblasts (CAFs) that remodel the extracellular matrix (ECM). Desmoplasia fuels a vicious cycle of stromal dissemination enriching both CAFs and desmoplastic ECM. Targeting specific drivers of desmoplasia, such as CAFs, either enhances or halts tumor growth and progression. These conflicting effects suggest that stromal interactions are not fully understood. This review highlights known fibroblastic-ECM interactions in an effort to encourage therapies that will restore cancer-restrictive stromal cues.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064819PMC
http://dx.doi.org/10.1016/j.ceb.2016.05.002DOI Listing
October 2016

A Chemomechanical Model of Matrix and Nuclear Rigidity Regulation of Focal Adhesion Size.

Biophys J 2015 Nov;109(9):1807-17

Department of Materials Science and Engineering, School of Engineering and Applied Science, The University of Pennsylvania, Philadelphia, Pennsylvania; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

In this work, a chemomechanical model describing the growth dynamics of cell-matrix adhesion structures (i.e., focal adhesions (FAs)) is developed. We show that there are three regimes for FA evolution depending on their size. Specifically, nascent adhesions with initial lengths below a critical value that are yet to engage in actin fibers will dissolve, whereas bigger ones will grow into mature FAs with a steady state size. In adhesions where growth surpasses the steady state size, disassembly will occur until their sizes are reduced to the equilibrium state. This finding arises from the fact that polymerization of adhesion proteins is force-dependent. Under actomyosin contraction, individual integrin bonds within small FAs (i.e., nascent adhesions or focal complexes) must transmit higher loads while the phenomenon of stress concentration occurs at the edge of large adhesion patches. As such, an effective stiffness of the FA-extracellular matrix complex that is either too small or too large will be relatively low, resulting in a limited actomyosin pulling force developed at the edge that is insufficient to prevent disassembly. Furthermore, it is found that a stiffer extracellular matrix and/or nucleus, as well as a stronger chemomechanical feedback, will induce larger adhesions along with a higher level of contraction force. Interestingly, switching the extracellular side from an elastic half-space, corresponding to some widely used in vitro gel substrates, to a one-dimensional fiber (as in the case of cells anchoring to a fibrous scaffold in vivo) does not qualitative change these conclusions. Our model predictions are in good agreement with a variety of experimental observations obtained in this study as well as those reported in the literature. Furthermore, this new model, to our knowledge, provides a framework with which to understand how both intracellular and extracellular perturbations lead to changes in adhesion structure number and size.
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http://dx.doi.org/10.1016/j.bpj.2015.08.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643201PMC
November 2015

Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer.

Trends Biotechnol 2015 Apr 20;33(4):230-6. Epub 2015 Feb 20.

Fox Chase Cancer Center, Cancer Biology, Temple Health, 333 Cottman Ave, Philadelphia, PA 19111, USA. Electronic address:

The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., dynamic reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations which, together with stromal changes including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma.
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http://dx.doi.org/10.1016/j.tibtech.2015.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380578PMC
April 2015

Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling.

Structure 2014 Dec 20;22(12):1810-1820. Epub 2014 Nov 20.

Developmental Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address:

Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.
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http://dx.doi.org/10.1016/j.str.2014.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255149PMC
December 2014

Engineering of tumor microenvironments.

Adv Drug Deliv Rev 2014 Dec 8;79-80:1-2. Epub 2014 Nov 8.

Cancer Biology, Fox Chase Cancer Center, 333 Cottman Av., R-W428 Philadelphia, PA 19111-2497, USA. Electronic address:

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http://dx.doi.org/10.1016/j.addr.2014.11.001DOI Listing
December 2014

Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6).

Mol Carcinog 2015 Oct 21;54(10):1122-31. Epub 2014 May 21.

Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

PACE4 (PCSK6) is a proprotein convertase (PC) capable of processing numerous substrates involved in tumor growth, invasion, and metastasis. Because of the human relevancy of the tobacco-associated carcinogen benzo[a]pyrene (B(a)P) we investigated whether transgenic mice in which this PC is targeted to the epidermis (K5-PACE4) may be more susceptible to B(a)P complete carcinogenesis than wild type (WT) mice. In an in vitro experiment, using cell lines derived from skin tumors obtained after B(a)P treatment, we observed that PACE4 overexpression and activity accounts for an increased proliferation rate, exaggerated sensitivity to the PC inhibitor CMK, and interference with IGF-1R autophosphorylation. Squamous cell carcinomas, obtained from K5-PACE4 mice subjected to complete chemical carcinogenesis, were characterized by a 50% increase in cell proliferation, when compared with similar tumors from WT mice. In addition, tumors from K5-PACE4 mice showed deeper invasion into the underlying dermis. Thus, mice overexpressing PACE4 exhibited tumors of increased growth rate and invasive potential when exposed to the human carcinogen B(a)P, further supporting the significance of PCs in tumor growth and progression.
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http://dx.doi.org/10.1002/mc.22183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240754PMC
October 2015
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