Tumor Biology and Microenvironment Research

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Breast cancer tumor and its microenvironment

Credit: National Cancer Institute \ Carbone Cancer Center at the Univ. of Wisconsin

Basic research supported by the Tumor Biology and Microenvironment Branch (TBMB) seeks to understand the role of tumor cells and the tumor microenvironment (TME) in driving cancer initiation, progression, maintenance and recurrence.  A comprehensive understanding of the tumor microenvironment, including stromal composition, cell-cell and cell-matrix interactions, and abnormal physiology, as well as cellular characteristics of heterogenous tumors is key to elucidating the complexities of cancer.  Understanding the cellular, molecular, and biochemical interactions of tumors within their microenvironment is essential to improving cancer diagnosis and treatment.

Research in this area is supported and directed by the Tumor Biology and Microenvironment Branch.

Tumor-Host Interactions and the TME

Understanding tumor growth and immune evasion requires characterization of the interactions of tumor cells with host tissue molecules and the host immune system. Bidirectional interactions between tumor cells and their microenvironment can promote tumor survival and aggressive cell behavior.

Key research areas include:

  • Tumor cell-mediated effects on the stromal microenvironment via release of cytokines/growth factors.
  • Tumor cell and stromal fibroblast-driven inflammation and its influence in the recruitment and function of immune cells in the TME.
  • Cell-cell and cell-matrix signaling driving tumor cell survival, proliferation, motility and invasion.

The complexities associated with signaling crosstalk pose a significant challenge in the clinic, especially within the context of disease recurrence. Studies dedicated to understanding therapy-associated compensatory pro-survival and pro-growth signaling are expected to help guide future treatments.

Extracellular Matrix and Tumor Progression

The extracellular matrix (ECM), a complex network of proteins, polysaccharides and growth factors, is a major component of the TME. Research in this area focuses on how the ECM becomes disorganized in cancer tissues and promotes cellular transformation.

Key research areas include:

  • Cells that alter the ECM during carcinogenesis, including stromal cells, such as cancer-associated fibroblasts (CAFs) and mesenchymal stem cells, immune cells, and epithelial cells.
  • The biomechanical properties of the ECM including how cells sense external forces, and how the increased stiffness of tumor stroma influences cancer progression.
  • Mechanisms by which abnormal ECM deregulates stromal cells via modulation of tumor-associated angiogenesis and inflammation.
  • Effects of abnormal cancer ECM on immune cell behaviors related to tumor progression.

Emerging areas include the role of exosomal delivery of ECM proteins, matrix remodeling enzymes, and cytokines in driving directional cell migration and the contribution of the ECM to the maintenance of stem cell properties.

Angiogenesis and Lymphangiogenesis

Research in angiogenesis focuses on tumor-induced vasculature, which provides oxygen and metabolites for tumor growth and progression. Studies on lymphangiogenesis examine the role of tumor-induced lymphatic vessels in tumor cell invasion and migration.

Key research areas include:

  • The network of growth factors and receptors induced by oncogenic, metabolic and inflammatory pathways that contribute to tumor angiogenesis.
  • Inducers of neovascularization including signaling pathways, membrane-derived molecules, secreted factors, and hypoxia.
  • Molecular strategies that promote vascular normalization to disrupt cancer progression.
  • Lymphatic vessel invasion and the interplay between a tumor and its lymphatic network.

Emerging areas relevant to this area include how altered endothelial cell-pericyte interactions, abnormal blood flow, and increased vascular permeability contribute to tumor heterogeneity, therapeutic resistance, and reduced immune responses.

Tumor Cell Plasticity

Tumor cells are highly adaptive and known to undergo genetic, epigenetic, and phenotypic changes throughout tumorigenesis. This leads to intra-tumoral heterogeneity, which is a significant challenge for current cancer therapies. TBMB supports studies aimed at better understanding the pre- and post-therapy induced mechanisms of tumor heterogeneity and therapeutic resistance. 

Key research areas include:

  • Mechanisms of epithelial-to-mesenchymal transition and its effects on tumor growth and invasion.
  • Epigenetic-based transcriptional reprogramming events driving phenotype switching, cancer stem cell enrichment, and therapy resistance.
  • The effects of inherent and acquired genetic alterations in tumor cells on survival, growth, and overall aggressiveness.
  • Single-cell analysis and mechanistic characterization of the tumor/TME landscape for drivers of lesions from premalignancy to advanced tumors.

Therapy-induced reprogramming of cancer cells is emerging as an important mechanism of resistance and recurrence. Studies evaluating “reversible” phenotypes modulated by epigenetic transcription factors in cancer cells may guide the identification of key therapeutic targets.

Cellular and Microenvironmental Aging in Tumors

Age is a well-recognized risk factor for cancer development, and older patients typically develop more aggressive and therapy-resistant tumors.  Evidence indicates that aging cells and the aging microenvironment play a direct role in driving tumorigenesis.

Key research areas include:

  • Mechanisms of age-related accumulation of senescent cells in tumors.
  • Effects of senescence-associated phenotypes and/or inflammation in tumor cell survival, angiogenesis and therapy resistance.

Older patients often respond less favorably and with higher toxicity to standard of care, which is emerging as a critically important area of research. Mechanistic studies in this realm help address important questions to ultimately improve cancer treatments during late adulthood.

Metabolic Reprogramming of the Tumor Microenvironment

Metabolic alterations in tumor stroma may represent early events that influence the adjacent tumor cells, and vice versa. Metabolic stromal reprogramming and how resultant metabolites affect tumor growth and progression are TBMB supported areas of research. 

Key research areas include:

  • Bidirectional alterations in tumor cell/stroma metabolism and its impact on tumor growth and progression.
  • Tumor cell-mediated metabolic reprogramming of stromal cells and tumor-associated inflammation.

Hormonal Signaling and Tumor Progression

Although abnormal hormonal signaling is associated with certain types of cancers and hormone therapy (which blocks hormonal signaling) is often used in cancer treatments, tumor cells can develop a hormone-resistant, aggressive phenotype. Research on hormonal signaling examines mechanisms that disrupt endocrine signaling pathways in tumor cells and microenvironmental cues that promote hormone-resistance during tumor progression.

Key research areas include:

  • Biology of hormone-resistant, aggressive tumors.
  • Mechanisms that change hormone-responsive tumors into invasive, hormone non-responsive tumors.
  • Identification of novel therapeutic targets of hormone non-responsive tumors.

Recent studies showed that protein-coding and noncoding RNAs may regulate hormone-resistant prostate cancer progression. Researchers are currently investigating molecular strategies to broaden the clinical utility of hormonal therapy to treat cancer.

Glycobiology

Research on the glycobiology of tumors explores how abnormal glycan modifications in cells promote malignant transformation.  Altered glycosylated structures on molecules in tumor cells impact cellular growth and migration processes involved in tumorigenesis. 

Key research areas include:

  • Characterization of glycans in tumor cells.
  • Role of glycan modifications in tumorigenesis.
  • Impact of abnormal glycosylation on tumor cell-microenvironment interactions.
  • Development of new, high-throughput technologies and experimental models to investigate glycobiology in the pathogenesis of cancer.

Emerging areas relevant to this research include elucidation of molecular pathways involved in aberrant glycosylation in tumor cells and examination of the cellular synthesis of glycans during tumor growth and invasion.

  • Updated: January 5, 2018

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