Understanding the developmental perspective of mammary lineage commitment to model breast cancer

Project summary: Breast cancer cells often reactivate embryonic developmental programs to execute multistep processes of tumorigenesis and metastasis. While the connections between breast cancer (BC) and mammary gland (MG) development are established, the initiation mechanisms of mammary tumorigenesis remain elusive. The insufficient understanding of mammary lineage commitment during development also imposes a significant challenge to model mammary tumorigenesis. During my postdoctoral career, I have developed an in vitro 3D organoid strategy to differentiate mouse embryonic stem cells (mESCs) into 3D mammary organoids that can secrete milk proteins in response to lactogenic hormones and undergo ductal branching in vivo following transplantation. This differentiation strategy now facilitates the exploration and targeting of mammary lineage genes active during development, revealing their involvement in breast cancer progression. In this project, I aim to use the mammary organoid paradigm to (a) identify embryonic mammary initiation factors regulating cell fate and contributing to breast cancer, (b) establish ESC-derived mammary organoids as a model for tumorigenesis, and (c) delineate the role of mammary lineage genes in breast cancer development. Employing single-cell transcriptomics and CRISPR genetic screening, I will identify genes involved in breast cancer initiation and progression while offering a high-throughput method for potential therapeutic exploration. I have assembled a team of senior scientists and experts in the field of breast cancer and organoids whose complementary expertise will help me to accomplish the research goals and assist me in the transition to establish my independent laboratory. The K99/R00 grant will provide me the time and funding to expand my scientific and experimental versatility. I will work under the mentorship of Dr. Shyam K. Sharan (genetic susceptibility factors in breast cancer) and co-mentored by Dr. Esta Sterneck (mammary gland development and breast cancer modeling) and Dr. Karl R. Koehler (Organoid biology). My advisory committee includes Dr. Senthil Muthuswamy (mammary organoids and cancer biology), Dr. David Salomon (oncofetal and growth factors in breast cancer), Dr. Benjamin T. Spike (embryonic mammary gland development), Dr. Sridhar Hannenhalli (Genomics expert and computational biologist), Dr. Raj Chari (CRISPR screening) and Dr. Tyler Malys (Biostatistics expert) who will help me with my scientific training and career progression. During the K99 phase, I will receive computational training on analyzing single cell RNA-sequencing data and CRISPR genetic screen, develop mentoring, leadership, grant writing and communication skills which will allow me to lead my independent research group. The members of my advisory committee have decades of experience in training postdoctoral fellows into tenure-track faculty positions, who will train me in academic job searches. Along with the scientific resources, the access to the cutting-edge technologies at NCI-Frederick will facilitate establishing my independent laboratory in the United States.