Deconstructing tumor heterogeneity: the stromal perspective.

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive suppressive stroma and how cellular composition and function may be altered during disease progression.

Understanding the tumor immune microenvironment (TIME) for effective therapy.

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy.

The Tumor Microenvironment at a Turning Point Knowledge Gained Over the Last Decade, and Challenges and Opportunities Ahead: A White Paper from the NCI TME Network.

Over the past 10 years, the Tumor Microenvironment Network (TMEN), supported by the NCI (Bethesda, MD), has promoted collaborative research with the explicit goal of fostering multi-institutional and transdisciplinary groups that are capable of addressing complex issues involving the tumor microenvironment. The main goal of the TMEN was to generate novel information about the dynamic complexity of tumor-host interactions in different organ systems with emphasis on using human tissues and supplemented by experimental models. As this initiative comes to a close, members of the TMEN took time to examine what has been accomplished by the Network and importantly to identify the challenges and opportunities ahead.

Meeting Report: The Role of the Mobilome in Cancer.

Approximately half of the human genome consists of repetitive sequence attributed to the activities of mobile DNAs, including DNA transposons, RNA transposons, and endogenous retroviruses. Of these, only long interspersed elements (LINE-1 or L1) and sequences copied by LINE-1 remain mobile in our species today. Although cells restrict L1 activity by both transcriptional and posttranscriptional mechanisms, L1 derepression occurs in developmental and pathologic contexts, including many types of cancers.

The National Cancer Institute's Efforts in Promoting Research in the Tumor Microenvironment.

The National Cancer Institute has fostered studies of the tumor microenvironment since 1993. Current funding initiatives that span concepts in cancer biology, technology development, convergence of physical sciences-oncology, and systems biology all support research that help in our understanding of the role of the tumor microenvironment at all stages of cancer progression and therapeutic resistance.

Protein microarray detection strategies: focus on direct detection technologies.

Protein microarrays are being utilized for functional proteomic analysis, providing information not obtainable by gene arrays. Microarray technology is applicable for studying protein-protein, protein-ligand, kinase activity and posttranslational modifications of proteins. A precise and sensitive protein microarray, the direct detection or reverse-phase microarray, has been applied to ongoing clinical trials at the National Cancer Institute for studying phosphorylation events in EGF-receptor-mediated cell signaling pathways.

Drosophila invasive tumors: a model for understanding metastasis.

Inactivation of Drosophila tumor suppressor genes can cause excessive proliferation and, in some cases, neoplastic growth. Neoplastic growth in Drosophila tissues can also be followed by metastasis upon transplantation into hosts or in vivo. Recently, we have shown that metastatic tumors of Drosophila can provide a model in which to identify genes that are involved in the metastatic process.

Drosophila screening model for metastasis: Semaphorin 5c is required for l(2)gl cancer phenotype.

Cancer metastasis is a complex process involving many genes and pathways. This complexity hinders the identification of molecules functionally required for this process. We have developed and used a Drosophila screening system to identify genes that are functionally important for tumorigenicity and metastasis.

Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities.

The exo-enzyme autotaxin/NPP2 (ATX/NPP2) is a potent stimulator of cell migration, invasion, metastasis, and angiogenesis. Recently, ATX/NPP2 was found to possess lysophospholipase D (lyso-LPD) activity, generating the bioactive mediator lysophosphatidic acid from precursors. In the present study, we used site-directed mutagenesis to delineate the active domain of lysophospholipid catalytic activity and to examine potential overlap with the nucleotide phosphodiesterase domain.