Edna Cukierman, PhD
Office Phone: 215-214-4218
Lab Phone: 215-214-4219
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.
- How to 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 (https://github.com/cukie/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.
- How desmoplasia affects 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 https://github.com/cukie/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.
- How to alter desmoplastic activity?
How does fibroblast matrix induce tumor progression?Video: Invasive cell motility through tumor-associated 3D ECMs under PI3K and/or β1-integrin inhibition This content requires the Adobe Flash Player.
Video: Invasive cell motility through tumor-associated 3D ECMs under PI3K
and/or β1-integrin inhibition - Montage of six hour time-lapse videos depicting
MDA-MB-231 cells invading through tumor-associated 3D ECMs (top left) in the
presence of 10 nM Wortmannin (top right), 50 μg/ml mAb13 (bottom left) or a
combination of both mAb13 and 10 nM Wortmannin (bottom right).