Elucidating the developmental origins of the mammary gland
Principal Investigator: Diwakar Pattabiraman, PhD
“I have a broad background in cancer biology, having worked on hematological malignancies during my graduate studies and breast cancers for my post-doctoral training. I am specifically trained in molecular cell biology, biochemistry, and mouse modeling of cancer, with a keen interest in understanding the mechanisms of malignant transformation and tumor progression.
As a graduate student in Australia, I laid the groundwork for revealing the mechanisms by which the Myb oncogene induces leukemic transformation of myeloid cells, developing expertise in study of hierarchy of the hematopoietic system, stem cell differentiation and dissecting the biochemistry of protein-protein interactions and post-translational modifications on transcription factor function. My contributions to the field have enabled a clearer understanding of how acute myeloid leukemia develops and paves the way for therapeutic targeting of the protein-protein interaction between Myb and p300 for leukemias.
Following my graduate work, I studied solid tumors and began working on tumor progression, metastasis, chemotherapy resistance and role of cancer stem cells in breast cancers. Through these studies, I have identified a novel role for PKA signaling, which when active, leads to the depletion of cancer stem cell activity. My research goals are to identify novel vulnerabilities of cancer cells that can be exploited for therapeutic targeting with a specific focus on differentiation therapy for solid tumors. We employ a combination of in-vivo models and epigenomic and transcriptomic analyses to develop an understanding of how cellular processes can be modulated for therapeutic gain.”
Project Description
The elucidation of cellular hierarchies that exist within adult tissues has been of utmost importance for our understanding of these biological systems. Several cellular hierarchies are sustained by a pool of adult stem cells that constantly replenish cell lineages as they differentiate e.g., hematopoietic stem cells (HSC). The study of HSC and their differentiation has become crucial to understanding the role that stem cells play in multiple age-related disorders, including leukemia1. Similarly, studying the mammary epithelial hierarchy is critical for understanding the relationship of breast carcinogenesis with various developmental lineages.
The identity of the stem/progenitor cell that initiates and sustains mammary development remains elusive, with conflicting reports about the existence of a bipotent stem cells vs. reports of multiple unipotent progenitors. The current study proposes to use in vivo CRISPR-Cas9 based barcoding systems to trace the origins of the mammary gland at both the embryonic and postnatal stages. This study will provide an unbiased ancestral map of the entire mammary gland, providing answers to previous debates in the field while shedding light on the various intermediate stages that primitive cell- types would need to traverse before attaining terminal differentiation.
We anticipate that uncovering the identity of the MaSc and elucidating the cellular hierarchy of the mammary gland will provide key insights into the cell-of-origin for mammary tumors, their metastatic descendants and the origins of tumor resistance.
