Patients diagnosed with cancer immediately want to know if their cancer has metastasized to other tissues, if any therapeutic and lifestyle strategies could have efficacy against their cancer, and if they will survive the disease. More than 90% of breast cancer patient deaths are due to metastatic tumors that are chemotherapy resistant and continue to thrive within a metastatic niche. Resistant cancer cells thrive within a metastatic microenvironment, where they avoid death by therapy. This microenvironment is composed of multiple cell types, proteins, and metabolites that support tumor growth. Identifying mechanisms by which cancer cells and their microenvironment together collaborate to regulate cancer progression and to defy therapies will identify vulnerabilities that can be targeted by new therapies and save lives.
The Littlepage Lab. The Littlepage research group studies how tumors evolve over time within physiological microenvironments (1) in response to treatment and (2) at the metastatic site. The long-term goal of my research is to identify factors that predict patient response to treatment and to develop therapeutic strategies targeting newly identified vulnerabilities in metastatic cells. We use an integrative in vivo temporal approach spanning normal mammary development, tumor progression, metastasis, and therapy resistance. Model systems include a combination of murine and human xenografts, cell culture and organotypic culture models, and systems biology approaches. Key accomplishments to date are the identification of undiscovered mechanisms by which the tumor microenvironment contributes to metastasis in lung and bone and new integrated approaches to identify and visualize metabolic vulnerabilities in tumors, including a sensor of nutrient availability and cellular stress that is an attractive therapeutic target.
The Littlepage Lab will continue research that integrates tumor microenvironment-mediated reprogramming of cancer cells with discovery-based approaches to uncover metabolic vulnerabilities and thereby provide alternative strategies for treatment of therapy resistant tumors. Critical to achieving this research goal is the ability to (1) develop models of the physiological response to cancer treatment in vivo, (2) spatially image tumor metabolites and tumor cell heterogeneity, (3) perturb in vivo pathways that influence response to treatment to test therapeutic efficacy, and (4) relate our findings to cancer patients.
Our research engages in a unique collaborative multi-disciplinary, translational preclinical research program that investigates cancer cells and the surrounding microenvironment across these platforms.
Some of our ongoing research projects include the following:
- Overcoming resistance to cancer therapies by studying the transcription factor ZNF217
- Metabolic reprogramming of breast cancer
- CXCL5/CXCR2 axis promotes breast cancer metastasis to bone
- Context specific effects of MMP3 in cancer metastasis
- Breast cancer disparities research in Kenya
- Peptide targeted liposomal nanoparticle-based drug delivery
The Microenvironment. Cancer malignancies continually adapt to the changing epithelium and the surrounding tumor microenvironment, or stroma, in order to survive and spread outside of the primary tissue. In normal human mammary glands, the epithelium is highly organized. These glands have intact lumens, an intact basement membrane, and surrounding stromal cells. During cancer progression, some of these cells undergo progressive changes. Tumors develop by utilizing normal developmental processes to promote survival and poor prognosis in patients. At each stage of tumor progression, the epithelium becomes exposed to a completely different set of cells and molecules, depending on its neighbors. This microenvironment promotes changes within the epithelium. This context is critical in being able to understand cancer and develop effective therapies.