Postdoc, Columbia University
I am a cancer engineer and I build in vitro models of pediatric cancers
My research interest is in an emerging area of bioengineering that is cancer engineering. The overarching goal of this field is to build controllable models that can faithfully recapitulate human cancer in vitro, by establishing a transdisciplinary approach that combines tools from molecular biology, bioengineering and medicine. The rationale behind this approach is that by better mimicking clinical situations, more reliable preclinical study results will be generated and better therapies will be developed.
Based on skills and knowledge that I acquired over the years, my line of research involves strong expertise in epigenetics, cancer, stem cell biology and bioengineering. Specifically, I am interested in drug-resistance and tumor relapse. Tumor relapse is the major cause of succumbing to the disease, and properties attributed to cancer stem-like cells, such as drug-resistance and cell plasticity, seem to be the key mechanisms. However, the lack of controllable models that recapitulate human cancer features limits our understanding of the process and impedes the development of new therapies. I recently demonstrated the undesirable effect of current treatments (isotretionin) in neuroblastoma. I showed the existence of resistant sub-populations of neuroblastoma cells with different levels of stemness that could be related to the capacity to transdifferentiate into endothelial-like cells. Formation of a new and alternative vascular network, for which there is no effective therapy, could explain in part the lack of clinical benefit observed with isotretinoin in the treatment of high-risk neuroblastoma. Tissue-engineered tumor models could thus bridge the gap between current in vitro cultures and animal models towards a better understanding of neuroblastoma tumor biology and development of new therapeutic modalities.
Abstract: Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
Pub.: 04 Sep '07, Pinned: 17 Aug '17
Abstract: Adipose-derived stem cells (ASCs) are multipotent and, thus, are an attractive cell source for tissue engineering and regenerative medicine. However, ASCs can also differentiate into myofibroblasts, a cell type known to support tumorigenesis, yet the mechanisms underlying the myofibroblastic differentiation of ASCs and the resulting consequences on tumor pathogenesis are not well understood. This knowledge deficit is due, in part, to a lack of 3D culture models that capture the biological and physical heterogeneity of the microenvironment that influences ASC fate under both physiological and pathological conditions. Advanced biomanufacturing strategies offer new opportunities toward the generation of in vivo-like 3D culture environments that can help study how some of these conditions regulate ASC fate. This review discusses the pro-tumorigenic plasticity of ASCs in the tumor microenvironment as well as other disease contexts (e.g., obesity and aging) and highlights advanced biomanufacturing technologies that could be used to integrate stromal parameters into the next generation of engineered 3D tumor models. Such models will enable new insights into ASC-dependent microenvironmental aspects contributing to tumor initiation and progression that may ultimately be targeted for improved anticancer therapies.
Pub.: 01 Aug '16, Pinned: 17 Aug '17
Abstract: There is a growing interest in the pivotal role of exosomes in cancer and in their use as biomarkers. However, despite the importance of the microenvironment for cancer initiation and progression, monolayer cultures of tumor cells still represent the main in vitro source of exosomes. As a result, their environmental regulation remains largely unknown. Here, we report a three-dimensional tumor model for studying exosomes, using Ewing's sarcoma type 1 as a clinically relevant example. The bioengineered model was designed based on the hypothesis that the 3-dimensionality, composition and stiffness of the tumor matrix are the critical determinants of the size and cargo of exosomes released by the cancer cells. We analyzed the effects of the tumor microenvironment on exosomes, and the effects of exosomes on the non-cancer cells from the bone niche. Exosomes from the tissue-engineered tumor had similar size distribution as those in the patients' plasma, and were markedly smaller than those in monolayer cultures. Bioengineered tumors and the patients' plasma contained high levels of the Polycomb histone methyltransferase EZH2 mRNA relatively to their monolayer counterparts. Notably, EZH2 mRNA, a potential tumor biomarker detectable in blood plasma, could be transferred to the surrounding mesenchymal stem cells. This study provides the first evidence that an in vitro culture environment can recapitulate some properties of tumor exosomes.
Pub.: 10 Jun '16, Pinned: 17 Aug '17
Abstract: Monolayer cultures of tumor cells and animal studies have tremendously advanced our understanding of cancer biology. However, we often lack animal models for human tumors, and cultured lines of human cells quickly lose their cancer signatures. In recent years, simple 3D models for cancer research have emerged, including cell culture in spheroids and on biomaterial scaffolds. Here we describe a bioengineered model of human Ewing's sarcoma that mimics the native bone tumor niche with high biological fidelity. In this model, cancer cells that have lost their transcriptional profiles after monolayer culture re-express genes related to focal adhesion and cancer pathways. The bioengineered model recovers the original hypoxic and glycolytic tumor phenotype, and enables re-expression of angiogenic and vasculogenic mimicry features that favor tumor adaptation. We propose that differentially expressed genes between the monolayer cell culture and native tumor environment are potential therapeutic targets that can be explored using the bioengineered tumor model.
Pub.: 22 Apr '14, Pinned: 17 Aug '17
Abstract: Drug toxicity often goes undetected until clinical trials, which are the most costly and dangerous phase of drug development. Both the cultures of human cells and animal studies have limitations that cannot be overcome by incremental improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. An area that could greatly benefit from these models is cancer research.In this review, the authors first describe the engineered tumor systems, using Ewing's sarcoma as an example of human tumor that cannot be predictably studied in cell culture and animal models. Then, they discuss the importance of the tissue context for cancer progression and outline the biomimetic principles for engineering human tumors. Finally, they discuss the utility of bioengineered tumor models for cancer research and address the challenges in modeling human tumors for use in drug discovery and testing.While tissue models are just emerging as a new tool for cancer drug discovery, they are already demonstrating potential for recapitulating, in vitro, the native behavior of human tumors. Still, numerous challenges need to be addressed before we can have platforms with a predictive power appropriate for the pharmaceutical industry. Some of the key needs include the incorporation of the vascular compartment, immune system components, and mechanical signals that regulate tumor development and function.
Pub.: 11 Feb '15, Pinned: 17 Aug '17
Join Sparrho today to stay on top of science
Discover, organise and share research that matters to you