Breast Cancer

Current Projects
Lauren E. Cote, PhD

Dr. Cote is exploring embryonic development to better understand how cells cooperate and build complex tissues. Since cancer cells often erroneously redeploy developmental programs and behaviors, her research into how neighboring cells align will yield insights into how cancerous cells metastasize and invade other tissues. Dr. Cote is combining tissue-specific genetic manipulations and laser cell ablations with live imaging during Caenorhabditis elegans digestive tract development to reveal how intracellular organization in one cell type can influence the alignment, polarity, and function of cells in the neighboring tissues.

Project title: "Constructing one continuous digestive tract, cell by cell"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Jessica L. Feldman, PhD
Cancer Type: Gastric, Other Cancer, Breast, Colorectal, All Cancers
Research Area: Developmental Biology
Luisa F. Escobar-Hoyos, PhD

Current pancreatic cancer chemotherapies are not effective, and targeted therapies are only applicable in about 5% of cases. Furthermore, pancreatic cancers cause immune cell stress, limiting the success of immunotherapies in this disease. Using animal models and tumor samples from pancreatic cancer patients, Dr. Escobar-Hoyos [William Raveis Charitable Fund Innovator] has discovered that changes in RNA splicing, a process that controls protein diversity in cells, are crucial for pancreatic cancer development, therapy resistance, and disruption of anti-tumor immunity. The proposed project will dissect the molecular role of RNA splicing in pancreatic cancer, which likely drives the disease's lethality. She seeks to develop a novel anti-RNA splicing therapy with dual action-a targeted therapy against tumor cells coupled with an immunotherapy to restore immune cell anti-tumor activity-to more effectively treat pancreatic cancer patients.

Project title: "Understanding RNA splicing in tumor-cell adaptation and anti-tumor immunity"
Institution: Yale University School of Medicine
Named Award: William Raveis Charitable Fund Innovator
Award Program: Innovator
Cancer Type: Breast, Lung, Pancreatic
Research Area: Cell Biology
Siting Gan, PhD

Dr. Gan focuses on brain metastasis in lung and breast cancer, a major cause of death for these patients. She is applying the latest single-cell technologies and developing computational tools to dissect how tumor cells interact with resident brain cells to mediate the progression of metastasis. This research aims to better understand the formation of brain metastasis which may lead to new therapeutic strategies for prevention.

Dr. Gan is developing computational methods to leverage the approximate spatial information of whether a brain cell is near a metastatic tumor cell and coarse tumor progression indicators, such as the postinoculation time and whole-brain ex vivo bioluminescence signal to infer the trajectories of phenotypic states in each type of cell. She is applying these methods to examine how the different populations of cells influence each other to co-evolve along their respective trajectories.

Project title: "In situ single-cell dissection of the tumor-microenvironment interplay mediating brain metastasis"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Joan Massagué, PhD, and Dana Pe'er, PhD
Cancer Type: Brain, Breast, Lung
Research Area: Systems Biology
Cong Ma, PhD

Patients with the same cancer diagnosis may experience very distinct disease progressions and treatment responses. These differences between patients have been associated with their degree of intra-tumor heterogeneity-the genetic, epigenetic, spatial, and environmental differences between the tumor cells. Characterizing the genetic and epigenetic states of different tumor cells is key to understanding how intra-tumor heterogeneity influences tumor progression, expansion, metastasis, and treatment response. Recent advances in single-cell RNA sequencing and spatial transcriptomics (which shows the spatial distribution of RNA molecules within a tissue sample) provide new opportunities to study intra-tumor heterogeneity in higher resolution. Dr. Ma's research aims to characterize intra-tumor heterogeneity in terms of specific genetic and epigenetic measures, and eventually develop 3D tumor models that capture this heterogeneity across multiple cancer types. Dr. Ma received her BS from Zhejiang University and her PhD in computational biology from Carnegie Mellon University.

The proposed computational methods will be based on previous methods developed in the group. Dr. Ma will develop a better method for identifying tumor clones for spatially resolved transcriptomics (SRT) data using both copy number and allele information using HMM and HMRF. She will adapt optimal transport frameworks and include biological networks as prior knowledge for integrating epigenetic data with SRT and between SRT slices to construct 3D spatial tumor multi-omics models.

Project title: "Modeling spatial organization and interactions among genetic and epigenetic states across cancer types"
Institution: Princeton University / Washington University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Benjamin Raphael, PhD (Princeton University), and Li Ding, PhD (Washington University)
Cancer Type: Breast, Pancreatic, All Cancers
Research Area: Quantitative Biology
Manuel Osorio Valeriano, PhD

Human cells compact their vast genomes into the small confines of the nucleus by wrapping their DNA into a highly complex structure called chromatin. Packaging DNA into chromatin, however, affects all nucleic acid-transacting machines (e.g., transcription factors) that need to access the genomic information stored in the DNA. NuRD is a large multi-subunit protein complex that plays a major role in making chromatin either accessible or inaccessible. Dysregulation of NuRD and aberrant targeting of the complex can result in the emergence of several types of cancers, including breast, liver, lung, blood, and prostate cancers. Dr. Osorio Valeriano’s [Philip O'Bryan Montgomery, Jr., MD, Fellow] work will reveal mechanistic aspects of NuRD-mediated chromatin regulation and pave the way for the development of novel therapeutic approaches that target cancers more effectively. Dr. Osorio Valeriano received his PhD from Philipps University and his MSc and BSc from the National Autonomous University of Mexico.

Project title: "Molecular and structural basis of gene expression regulation by the nucleosome remodeling and deacetylase (NuRD) complex in human cancer"
Institution: Harvard Medical School
Named Award: Philip O’Bryan Montgomery Jr. MD Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Lucas Farnung, PhD, and Danesh Moazed, PhD
Cancer Type: Blood, Gastric, Breast, Lung, Prostate
Research Area: Structural Biology
Tristan Wold Owens, PhD

Dr. Owens [Suzanne and Bob Wright Fellow] focuses on heat shock proteins (HSPs) and their “master regulator” called heat shock transcription factor 1 (HSF1). The transformation and growth of cancers causes a wide array of cellular stresses including metabolic changes, genomic instability, and protein misfolding that would halt the growth of a normal cell. Tumor cells, however, depend on cellular stress response machinery, like HSPs, for their survival. HSF1 is critical to tumor development and progression, and HSF1 activity is strongly correlated with poor prognosis in many common cancers. For decades, efforts to develop cancer therapies targeting HSPs have failed. Dr. Owens aims to understand how HSPs and HSF1 interact to regulate activity, and how this regulation is co-opted to promote tumor growth and progression.

Project title: "Molecular mechanisms of heat shock transcription factor 1 in cancer"
Institution: University of California, San Francisco
Named Award: Suzanne and Bob Wright Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): David A. Agard, PhD
Cancer Type: Other Cancer, Breast, Prostate, All Cancers
Research Area: Biochemistry
Sangeetha M. Reddy, MD

Despite the success of immunotherapies such as immune checkpoint blockade in other solid tumors, breast cancer patients have shown limited responses, especially in cases of metastatic disease. Antigen-presenting cells, critical to initiate anti-tumor immunity and for efficacy of immune checkpoint blockade, are known to be defective in breast cancers. Dr. Reddy's [Katelyn Shea Butts Memorial Research Award/William Raveis Charitable Fund Clinical Investigator] research focuses on restoring effective antigen presentation to enhance anti-tumor immunity in breast cancers. Based on data generated in her lab, she is leading a clinical trial to test the combination of chemotherapy with two therapeutic molecules that promote different aspects of antigen presentation. This trial will assess the safety, clinical efficacy, and pharmacodynamics associated with this triplet therapy. Through this work, she hopes to improve long-term survival of patients with triple negative breast cancer and lay the foundation for systemically targeting antigen presentation as a therapeutic strategy in solid tumors.

Project title: "Multi-modality approach to enhancing antigen presentation in breast cancers"
Institution: University of Texas Southwestern Medical Center
Named Award: Katelyn Shea Butts Memorial Research Award/William Raveis Charitable Fund Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Zhijian (James) Chen, PhD, and Hans Hammers, MD, PhD
Cancer Type: Breast
Research Area: Immunotherapy
Jamie B. Spangler, PhD

Groundbreaking advances in immunotherapy have revolutionized the treatment of cancer. In particular, new antibody drugs that block immunosuppressive pathways have achieved remarkable success in reawakening the immune system to clear tumor cells, leading to lasting cures in patients whose cancers do not respond to any other therapies. Unfortunately, the majority of patients (>70%) do not respond to immunotherapy treatment. It is difficult to predict which patients will benefit, creating an urgent demand for novel immunotherapy drugs that act through alternative mechanisms. Dr. Spangler is working to develop a class of antibody therapeutics that target cancer-promoting pathways in a different way than all current immunotherapies, with the goal of drastically expanding the percentage of cancer patients who benefit from them.

Project title: "Engineered multispecific down-regulating antibodies to advance cancer immunotherapy"
Institution: Johns Hopkins University
Award Program: Innovator
Cancer Type: Breast, Colorectal, All Cancers
Research Area: Immunotherapy
Runmin Wei, PhD

Dr. Wei is focusing on inflammatory breast cancer (IBC), an aggressive disease subtype without known genetic signatures. This suggests that IBC could be highly heterogeneous (the cells within a tumor are genetically diverse), and the tumor microenvironment (the environment surrounding a tumor) may be important for disease progression and therapeutic resistance. He is developing a computational toolkit to characterize the IBC tumor spatial heterogeneity and tumor microenvironment. He will leverage cutting-edge deep learning approaches to associate histopathology findings from tumor samples with single cell spatial sequencing information. This project will provide a better understanding of IBC initiation, progression and therapy responses at a molecular level.

Dr. Wei will use open-access single cell and spatial sequencing data analysis tools, e.g. Seurat and Scanpy to analyze data. He will also use specific computational tools for different analytical purposes, e.g. RNA Velocity and Monocle to infer cell differentiation, CytoTRACE, SCENT to infer cell differentiation potentials, and SCENIC to infer the transcriptional factors and gene regulatory network. Besides, he will develop novel algorithms/computational tools for spatial and single-cell sequencing data analysis.

Project title: "Integrating single cell genomic and spatial information to delineate tumor heterogeneity and microenvironment interactions in inflammatory breast cancer"
Institution: The University of Texas MD Anderson Cancer Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Nicholas E. Navin, PhD, and Ken Chen, PhD
Cancer Type: Breast
Research Area: Bioinformatics
Xiphias Ge Zhu, PhD

Many immunotherapy strategies require patient T cells to recognize specific cancer-associated antigens. However, it is unclear what these antigens are and how they contribute to tumor shrinkage during treatment. Dr. Zhu [HHMI Fellow] will use large-scale antigen screening methods to identify cancer-associated antigens recognized by T cells that are activated in breast cancer patients during immunotherapy treatment. Mapping the antigen landscape of breast cancer will identify targetable antigens and improve future immunotherapies. Dr. Zhu received his PhD from The Rockefeller University and his BSc from the National University of Singapore.

 
Project title: "Charting the tumor antigen landscape of breast cancer"
Institution: Brigham and Women's Hospital
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Stephen J. Elledge, PhD
Cancer Type: Breast
Research Area: Tumor Immunology
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