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Trainee Spotlight: Janusz Franco-Barraza, MD, PhD
Since my early days in school, I have been fascinated by the human body’s ability to respond to internal and external insults, and to function as a self-renewing biological machine. These interests were initially fueled by reading Paul de Kruif’s "Microbe Hunters", which preached that behind every disease exists a complicated interplay between internal and external processes. This duality has driven my training and defined my current research focus: namely, interplay between the internal and external forces interacting between cancer cells and the surrounding tissue, often referred to as tumor microenvironment cross-talk.
During my early training, some influential characters convinced me to pursue a career in science. One was my father, an enthusiastic pathologist who guided the first steps of my medical training. The second was Prof. L. Benitez, who, during a visit to my medical school, Juarez University of Durango State, in Durango, Mexico, triggered my fascination for cancer biology. Years later, he, together with Prof. I. Meza, became one of my PhD mentors at the Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), in Mexico City, Mexico, where I studied the influence of external (i.e. tumor microenvironment-originated) inflammatory molecules in the phenotype of cancer cells.
My story at Fox Chase Cancer Center started in September 2009, when I joined Dr. Edna (Eti) Cukierman’s lab. Since then, it has been a great three-dimensional (3D) adventure learning how non-cancerous cellular and extracellular components surrounding the cancer cells (named together as the tumor stroma), and in particular the fibrous elements known as the extracellular matrix (ECM), influence tumor growth and cancer progression. Under Dr. Cukierman’s guidance, I have developd in vivo-like 3D miroenvironment models of human cancer, and then used these models to investigate how the main ECM receptors—integrins—trigger carcinoma-associated fibroblasts (CAF) to take on an active fibroblastic phenotype and influence pancreatic and renal carcinomas to progress. My recent findings suggest that the levels and quality of activation of specific integrins by tumor-permissive ECM (permissive-ECM) may predict tumor progression. In summary, I am interested in discovering cancer and stroma interaction cues, which could, eventually, be translated into the clinic as prognostic biomarkers for cancer progression, and novel targeted therapies.
In addition to malignant cells, tumor masses are composed of non-malignant cells and fibrous components, known collectively as the tumor stroma. Interestingly the tumor stroma may promote or restrict tumor progression depending on the quality of stromal activity (i.e. secreted ECM composition). My research focuses on understanding how the tumor stroma encourages tumor progression with the ultimate goal of designing novel strategies to manipulate, and rewire this stroma to induce, a tumor-restrictive environment. To study these cancer and stroma interactions, we first developed a 3D culture system to ovecome the artifacts that arise from two-dimentional cell culture systems. By isolating fibroblastic cells (the main ECM producer cells in vivo) from cancer patients, culturing them in multilayers, and supporting the secretion and polymerzation of extracellular matrix components, we obtained 3D ECM substrates. These 3D systems recapitulate many of the composition and architectural characteristics of the in vivo tumor stroma, while also being readily adaptable to investigating cancer cell responses to tumor-restrictive and –promoting environments (Franco Barraza et al. Curr Protoc Cell Biol. 2016). The flexibility of this system has allowed me to study the type of signals imparted by the tumor-ECM, which could be targeted to restrict cancer progression.
The role of the tumor-ECM is very relevant in those tumor masses that present a dense tumor stroma activity, characterized by an excessive ECM deposition (known as desmoplastic reaction). Pancreatic carcinoma (PDAC) is one of the most aggressive cancers known, and it is accompanied by a dense desmoplastic reaction of its stroma, which has been blamed for this cancer’s resistance to chemotherapy and tumor progression. To understand the role of the tumor stroma in PDAC, I studied PDAC cells in tumor-restrictive and –permissive environments. From these studies, I discovered an important interplay of integrin molecules triggered by the permissive-ECM. Specifically, this ECM controls αvβ5-integrin signaling, which prompts the accumulation of activated α5β1-integrin pools in specific intracellular vesicles. Additionally, I complemented these findings with a detailed analysis of well annotated clinical samples of PDAC and renal carcinoma patients. In those studies, I used a novel integrative approach combining multi-colored molecular detection of the mentioned molecules, in combination with other tumor-stroma markers and a new quantitative algorithm. We defined two readily distinguishable desmoplastic phenotypes in these patients that correlated with markedly distinct clinical outcomes, a tumor-permissive and a tumor-restrictive (Franco Barraza et al. Elife. 2016). Moreover, these findings suggested a potentially general mechanism sustaining a desmoplastic stroma, and opened the possibility to manipulate molecular candidates in these tissues, in order to stabilize tumor-restrictive, or to revert tumor-permissive stroma in these patients.
In summary, better understanding of the mechanism behind the mentioned phenomena, and the design of customized therapies for cancer patients, could signify a new way to provide the human body with effective means to overcome malignant insults.
Franco-Barraza J, Beacham DA, Amatangelo MD, Cukierman E. Preparation of Extracellular Matrices Produced by Cultured and Primary Fibroblasts. Curr Protoc Cell Biol. 2016 Jun 1;71:10.9.1-10.9.34. doi: 10.1002/cpcb.2.
Franco-Barraza J, Francescone R, Luong T, Shah N, Madhani R, Cukierman G, Dulaimi E, Devarajan K, Egleston BL, Nicolas E, Katherine Alpaugh R, 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 Jan 31;6. pii: e20600. doi: 10.7554/eLife.20600.