Landon Foundation-AACR INNOVATOR Award for Research in Tumor Microenvironment
The Landon Foundation-AACR INNOVATOR Award for Research in Tumor Microenvironment was established to recognize the outstanding achievement of a junior faculty-level scientist working in the tumor microenvironment field, and support his or her research that, if successful, will have potential to advance knowledge on the tumor microenvironment. The goal of the grant program is to encourage junior faculty who are in the first five years of a faculty appointment (at the start of the grant term) to pursue novel tumor microenvironment research. Travel support is included to help foster interactions and collaborations among cancer scientists studying various aspects of cancer biology and to disseminate scientific knowledge about tumor microenvironment research within the field. Proposed projects may be basic, translational, clinical, or epidemiological in nature and must focus on the study of various aspects of the tumor microenvironment; including, but not limited to, the role of stroma and extracellular matrix in tumor development, angiogenesis, immunity and inflammation in the tumor microenvironment, as well as approaches to therapeutically target the tumor environment.
Ken S. Lau, PhD
Vanderbilt University Medical Center
Systematic dissection of an inflammatory niche for cancer initiating cells
The immune microenvironment is an important factor in cancer progression, prognosis, and response to immunotherapy. Tumor microenvironments are complex, composing of multiple cell types with different potential to communicate with cancer cells. How different inputs influence cancer cells to positively or negatively impact their behaviors remains an undefined, complex problem. Specifically, the spatial organization of immune cells and their proximity of cancer cells have not been exploited for biological investigation. Dr. Lau's research is focused on how networks of immune cells proximal to cancer cells influence their differentiation status and cancer stem cell potential.
It is commonly suggested that the recurrence of solid cancers is attributed to cancer stem cells that have the ability to evade therapy and metastasize to other tissues. Specifically, differentiation from stem-like cells contributes to tumor heterogeneity and subsequent therapeutic resistance. Colorectal cancer is thought to be initiated from stem cells residing in the crypts of Lieberkuhn, and thus, a potential source of cancer stem cells may be stem cell progenies of the cell of origin. However, recent studies have shown that differentiated cells can also initiate intestinal tumors by dedifferentiating into a stem-like state in an inflammatory context.
Dr. Lau's research will focus on innovating technologies to: 1) profile signaling states and cell identities of cancer cells to characterize their responses to their microenvironments and differentiation potential at single cell resolution, and to 2) determine the locations, identities, and secretory profiles of different inflammatory cell types that modulate cancer cell differentiation potential. Single cell data describing communication between individual immune and epithelial constituents will be modeled computationally using graph theoretical analyses. These approaches will be used, first to understand microenvironmental influences in well-controlled mouse models of colorectal cancer initiated specifically from stem cells or differentiated cells. Subsequently, our approaches will be applied to human patient cohorts to build models relating mutational status, microenvironment profile, cancer cell states, and finally patient outcomes. Our efforts will result in significant advances in the pathological characterization of tumors, patient stratification, and will also identify critical interactions in the tumor microenvironment signaling network that can be targeted for therapeutic design.
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Sergei I. Grivennikov, PhD
Assistant Professor, Cancer Prevention and Control Program
Fox Chase Cance Center
The Role and Mechanisms of Tumor Promoting, IL-17 Dependent Inflammation
There is a well-documented connection between inflammation and cancer, with chronic inflammation preceding the development of approximately 15-20 percent of all cancers. However, actually the majority of all solid tumors demonstrate a paradoxical ability to recruit inflammatory cells and to upregulate inflammatory mediators, such as cytokines, to aid tumor progression. During his earlier work, Dr. Grivennikov and colleagues defined this process as "tumor elicited inflammation’" (TEI) and suggested that in colorectal cancer (CRC), TEI is induced early during the process of CRC tumorigenesis, particularly because of the oncogene-induced, tumor site-specific deterioration of epithelial barrier and translocation of microbial products into the tumor.
Despite its obvious pathophysiological importance in cancer, the mechanisms of TEI maintenance and pro-tumorigenic action within the tumor microenvironment in tumor progression have not yet been studied. Production of IL-17 cytokine has been characterized as one of the important events in TEI induction in CRC and in stage I/II CRC patients is associated with poor prognosis. During the time of this award, Dr. Grivennikov’s lab will employ a variety of genetic mouse models and in vivo approaches to study CRC progression and the role of IL-17 mediated TEI in these CRC progression and metastasis. He aims to uncover the distinct molecular and cellular mechanisms of TEI (particularly mediated by IL-17) action during different stages of CRC. In particular, IL-17 producing and IL-17-responsive cells will be better defined and the distinct contribution of IL-17 to tumor growth, invasion and metastasis will be examined. Dr. Grivennikov also plans to study the role of various environmental factors in induction of “strong” or “weak” IL-17 mediated TEI in growing tumors. This project will pave the road to more comprehensive attempts to characterize the phenomenon of TEI in different types of cancer. Likely, similar or identical mechanisms will be found to operate in other solid malignancies and, therefore, findings of this project can be also applied to other types of cancers. Finally, this project will uncover new targets (related to inflammatory pathways) within the tumor microenvironment for future therapeutic and preventive approaches.
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