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New Target Could Starve Cancer and Activate Immune System in Fight Against Pancreatic Cancer
Researchers at Fox Chase Cancer Center have identified a new biomarker and potential novel treatment target for pancreatic ductal adenocarcinoma (PDAC) that could help starve cancer cells and allow the immune system to attack the tumor. Read the full article here.
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 Matrix Biology (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. Award, 2019, 2020, and 2021
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
Cellular and signal transduction mechanisms of fibrous desmoplastic activation, maintenance, and function
Pancreatic, lung, renal, and other transformative alterations regulated by cancer-associated fibroblasts (CAFs) 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 (known as CDMs) and biomimetic material engineering
The main goal of the Cukierman Lab is to study the biology of desmoplasia. Akin to chronic wounds driven by changes in fibroblastic cell functions, desmoplasia plays a central role in epithelial tumorigenesis. The team research focuses on the study of the bi-directional exchange of information that is produced by cell-extracellular matrix (ECM) contacts known as “three-dimensional matrix adhesions” or 3D-adhesions. Special interest is placed in understanding how desmoplastic 3D-adhesions, formed between cancer-associated fibroblasts (CAFs) and the interstitial ECM, transduce signals that drive pro-tumor effects.
Cukierman has previously developed a normal fibroblastic primary cell-derived, as well as a primary CAF-derived 3D ECM system, known as CDM, which simulates human desmoplastic stroma progression of epithelial cancers like pancreas, lung, kidney, and more. The team uses CDMs to investigate mechanisms of ECM-induced CAF activation, and the reciprocal effects imparted by CDMs and CAFs that regulate tumor cell invasion, growth, immunosuppression, axonogenesis, drug efficacy, and others.
Tissue engineering methodologies serve to question the topographical/architectural vs. biochemical aspects of desmoplasia. Pre-clinical animal models serve to test stromal targeting drugs, while laboratory discoveries are validated in human pathological samples via simultaneous multiplex immunofluorescence. For this, the Cukierman team developed a special analysis software, SMIA-CUKIE. Multidisciplinary approaches used by this team incorporate molecular biology, biochemical and cell-based assays, laser scanning confocal and multiphoton microscopy, real time multiplex immunofluorescence, quantitative digital imaging analyses, genetic manipulations, tissue patterning, mathematical modeling, and other methodologies.
Importantly, clinical collaborations facilitate testing laboratory-generated hypotheses while translating basic discoveries to the clinic.
Central premise: We postulate that it is possible to reprogram the desmoplastic microenvironment back to its natural 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. Ongoing efforts in the lab actively test this hypothesis from a tumor microenvironment perspective. The goal is to attempt finding means to control desmoplastic activity in a way that these processes could limit pro-tumoral stroma functions yet harness the natural anti-tumor functions of the microenvironment.
We initially demonstrated that desmoplastic extracellular matrices (ECMs) induce an active myofibroblastic phenotype upon naive fibroblastic cells (Amatangelo et al 2005). Using syngeneic human fibroblasts harvested from patient-matched normal and tumor surgical samples, we are able to 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 cell autonomous desmoplastic fibrillogenesis from mechanisms of ECM and other extracellular factors that regulate fibroblastic function. This way, we can use our multicellular culturing system to study how cancer-associated fibroblasts (CAFs) use their ECMs in a reciprocal manner to provide nutrition to cancer cells under nutritional stress, impart immunosuppressive local influences, and communicate with other cells in a way that these nurture tumorigenesis and/or deter drug efficacies.
Using the above-mentioned culturing system and validation of uncovered phenotypes in cohorts of pathological human samples, we uncovered signaling mechanisms that include TGFbeta regulation of desmoplastic ECM production as well as ECM controlled integrin signaling, distinct receptor recycling and cytoskeletal reorganization. The uncovered mechanisms control both pro- and anti-tumor CAF functions and are represented by a desmoplastic phenotype that is indicative of pancreatic and renal cancer patient outcomes (Franco-Barraza et al 2017).
The Cukierman team posits that “normalizing” the desmoplastic microenvironment could harness the natural anti-tumor stromal functions. Hence, a main goal is to be able to design means to impede tumor development and/or progression. To this end, the team uncovered that the pro-tumor CAF phenotype mentioned above, which is regulated by integrins and CAF-ECM, supports the expression of NetrinG1 (NetG1) in CAFs. Francerscone & Vendramini-Costa et al 2021, demonstrated that CAFs expressing NetG1 support cancer nutrition and deter anti-tumor immunity. The study found that CAFs expressing NetG1, but not CAFs that lack the expression of this protein, provide cancer cells with nutrition, and have the ability to sustain cancer cells under starving conditions that are similar to the conditions found in the pancreatic cancer microenvironment.
Secondary to these, the team also reported that while NetG1 loss (or its inhibition) does not change the amount or architectural appearance of the CAF ECM, it in fact changes the type of fibrous materials being produced in a way that these no longer serve as an added source of nutrition to starving cancer cells. As importantly, the Cukierman Lab also discovered that CAFs deficient in NetG1 have the ability to stop inhibiting, and in some cases even promote, anti-tumor immune responses. Excitingly, the team uncovered that NetG1 function stands on top of signaling pathways, which particular govern metabolic aspects of CAFs, as well as the ability of these cells to secrete factors that promote tumor growth, as well as factors that inhibit anti-tumor immunity. In order to effectively obstruct all these functions, it would be necessary to use a combination of drugs that can target each of the main signaling pathways governing all the functions. Yet, the team reported that simply blocking NetG1 in CAFs effectively and simultaneously limits these above-mentioned functions. In fact, using an anti-NetG1 antibody, the team was able to halt tumorigenesis in an orthotopic/syngeneic mouse model. If a similar drug was to be developed, it should have the potential to make a real difference, especially if combined with immune targeting and/or metabolic altering drugs.
In summary, the current focus of the Cukierman lab is to study the microenvironmental roles that NetG1 and NGL1 play in tumor development and progression.
Added projects use the simultaneous multiplex immunofluorescent approach, combined with other methods, to query if desmoplastic phenotypes indicative of pro-tumor or normalized stroma could be detected in patient biopsies (including liquid biopsies). These tests serve as laboratory correlates in clinical trials aiming to alter stromal function of solid epithelial cancers, such as pancreatic and other cancers.
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.
Francescone R≠, Barbosa Vendramini-Costa D≠, Franco-Barraza J, Wagner J, Muir A, Lau AN, Gabitova L, Pazina T, Gupta S, Luong T, Rollins D, Malik R, Thapa RJ, Restifo D, Zhou Y, Cai KQ, Hensley HH, Tan Y, Kruger WD, Devarajan K, Balachandran S, Klein-Szanto AJ, Wang H, El-Deiry WS, Vander Heiden MG, Peri S, Campbell KS, Astsaturov I, Cukierman E: Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast-driven nutritional support and immunosuppression. Cancer Discovery 2021, 11:446-79. (≠ equal contribution) PubMed
Alexander JI, Vendramini-Costa DB, Francescone R, Luong T, Franco-Barraza J, Shah N, Gardiner J, Nicolas E, Raghavan KS, Cukierman E: Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma. Sci Rep 2021, 11:3802. Open Access
Gabitova-Cornell L, Surumbayeva A, Peri S, Franco-Barraza J, Restifo D, Weitz N, Ogier C, Goldman AR, Hartman TR, Francescone R, Tan Y, Nicolas E, Shah N, Handorf EA, Cai KQ, O'Reilly AM, Sloma I, Chiaverelli R, Moffitt RA, Khazak V, Fang CY, Golemis EA, Cukierman E, Astsaturov I: Cholesterol Pathway Inhibition Induces TGF-beta Signaling to Promote Basal Differentiation in Pancreatic Cancer. Cancer Cell 2020, 38:567-83 e11. PubMed
Zhu Z, Achreja A, Meurs N, Animasahun O, Owen S, Mittal A, Parikh P, Lo T-W, Franco-Barraza J, Shi J, Gunchick V, Sherman MH, Cukierman E, Pickering AM, Maitra A, Sahai V, Morgan MA, Nagrath S, Lawrence TS, Nagrath D: Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours. Nature Metabolism 2020. PubMed, other link
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, 20:174-86. PubMed
Cheng Y, Franco-Barraza J, Wang Y, Zheng C, Zhang L, Qu Y, Long Y, Cukierman E*, Yang Z-j*: Sustained hedgehog signaling in medulloblastoma tumoroids is attributed to stromal astrocytes and astrocyte-derived extracellular matrix. Lab Invest 2020, 100:1208-22. (*Co-Corresponding) PubMed.
Padhi A, Singh K, Franco-Barraza J, Marston DJ, Cukierman E*, Hahn KM, Kapania RK, Nain AS*: Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction. Communications Biology 2020, 3:390. (*Co-Corresponding) PubMed
Ben Baruch B, Mantsur E, Blacher E, Franco-Barraza J, Cukierman E*, Stein R*: CD38 in cancer-associated fibroblasts promotes pro-tumoral activity. Lab Invest 2020, 100:1517-31. (*Co-Corresponding) PubMed
Alexander J, Cukierman E: Cancer associated fibroblast: Mediators of tumorigenesis. Matrix Biol 2020, 91-92:19-34. PubMed
Ruggeri JM, Franco-Barraza J, Sohail A, Zhang Y, Long D, Pasca di Magliano M, Cukierman E, Fridman R, Crawford HC: Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma. Am J Pathol 2020. PubMed
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. PubMed
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 Discovery 2019, 9:64-81. PubMed
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, 6:e20600. PubMed
Franco-Barraza J, Beacham DA, Amatangelo MD, Cukierman E: Preparation of extracellular matrices produced by cultured and primary fibroblasts. Curr Protoc Cell Biol 2016, Chapter 10:10.9.1-.9.34. 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, 167:475-88. PubMed
Cukierman E, Pankov R, Stevens DR, Yamada KM: Taking cell-matrix adhesions to the third dimension. Science 2001, 294:1708-12. PubMed