
Mark LaBarge Lab
Research Lab Overview
Professor Mark LaBarge’s Lab is dedicated to exploring how aging affects the mammary gland, increasing its vulnerability to cancer. Our goal is to understand the relationship between age-related changes in the breast's microenvironment and cancer risk. This understanding will aid in developing innovative methods for early cancer detection, risk assessment, and identifying potential preventive treatments.
The breast serves as an ideal model for studying aging's impact on human epithelial tissues. We obtain normal breast tissue from a broad age range of women, which is typically discarded during medical procedures. This tissue provides us with both stromal and epithelial cell types that we can grow in the lab. These primary cell cultures maintain the molecular characteristics of aging and lineage specificity found in the body. This capability allows for the sharing of valuable human tissue samples across research teams, facilitating repeated detailed studies. We investigate the effects of aging on these cells to understand how it influences cancer risk, including in women with inherited gene mutations that predispose them to cancer.
By bringing together a dedicated team of researchers, clinical research associates, and medical professionals, we have cultivated hundreds of cell strains from a wide array of individuals. Our aim is to integrate the study of population sciences with cellular and stem cell biology. This integration will enhance our understanding of how cancer susceptibility occurs on a broader scale, impacting populations rather than just individual cases.
Pathophysiological mechanisms of aging in normal breast that predispose women to breast cancer
Over 75% of new breast cancer diagnoses occur in women aged 50 and above, predominantly featuring tumors of the luminal subtype. When my research commenced around 2009, the prevailing understanding was that aging in the breast involved superficial changes, such as increased fat and estrogen receptor-positive cells, with normal breast tissue primarily serving as a comparative baseline to tumors. Our hypothesis suggests that age-related changes in the microenvironment could disrupt the function of mammary stem cells. This disruption may impair the healthy balance of breast tissue, undermining the body's natural defense against cancer.
Specifically, we've observed that the immune environment within the breast evolves with age towards a state less capable of fighting cancer (Journal of Mammary Gland Biology and Neoplasia, 2021). We believe this shift, marked by specific immune signals, might influence both the epithelial cells and the surrounding tissue structure. Our lab has developed over 100 lines of primary human mammary epithelial cells from women aged 16 to 91. These cells, capable of extensive growth, exhibit epigenetic markers that allow them to rebuild their own structural foundation in three-dimensional cultures without synthetic scaffolds (iScience, 2021).
Our research has further unveiled that the natural aging process can be distinguished from cell replication-related aging within these cells, preserving the intricate details of aging at the molecular and functional levels (Cancer Research, 2012; Cell Reports, 2018; Aging, 2017). This has led us to identify that with age, certain progenitor cells in the breast fail to develop into mature cells that help suppress tumor formation, suggesting a shift towards a less differentiated state that may increase cancer risk. We've found that changes in key signaling pathways during the transition to menopause may reduce these cells' ability to respond to environmental cues for differentiation (Cell Reports, 2014).
Further exploring the intersection of aging and cancer, our studies show that the age of mammary epithelial cells can influence the characteristics of cancer that develops, pointing towards age as a factor in determining cancer subtype (Frontiers, 2015). Advanced analytical techniques have helped us discover that aged luminal cells share molecular features with precancerous cells, suggesting that aging processes, rather than genetic mutations, may be pivotal in cancer development (Cell Reports, 2018).
We are pioneering the use of organoid models to study how aging affects mammary epithelial cells, uncovering patterns such as age-related DNA methylation that are passed on through mechanisms not directly involving cell-to-cell contact (Aging, 2017; bioRxiv, Sayaman et al., 2021). This comprehensive research aims to provide a deeper biological understanding of cancer susceptibility, potentially guiding future prevention and treatment strategies.
Delineating tissue specific biomarkers of aging as indicators of susceptibility to breast cancer, and identifying targetable vulnerabilities for breast cancer prevention
For a comprehensive breast cancer (BC) prevention strategy, identifying early detection biomarkers is crucial. We believe that aging biomarkers can pinpoint tissues at increased risk for cancer. In our search, traditional aging markers like telomere shortening showed limited relevance to aging in breast tissue (Genome Integrity, 2013). However, we've discovered three breast-specific aging biomarkers that link accelerated aging to a higher cancer risk.
First, by using microfluidic devices to analyze cell mechanics, we found that cells from older breast tissue share mechanical characteristics with non-cancerous, transformed cells (Nature Micro Nano, 2018). Second, we observed that with age, the expression of ELF5—a key transcription factor for breast development—decreases. This decrease correlates with DNA methylation changes at the ELF5 promoter. Interestingly, biological age estimates based on ELF5 in average-risk individuals closely match their chronological age. In contrast, individuals with BRCA1 or BRCA2 mutations, who are at a higher risk for BC, show a biological age significantly ahead of their chronological age by an average of 20 years (Cancer Prevention Research, 2021). This suggests ELF5-related changes as potential indicators of breast cancer risk.
Third, we've noted that aging luminal epithelial cells begin expressing markers typically found in myoepithelial cells, suggesting a loss of cellular identity. This accelerated aging phenotype is particularly evident in younger women with mutations in the BRCA1, BRCA2, or PALB2 genes, presenting early signs of aging such as increased luminal cells with myoepithelial markers and a bias towards basal differentiation (Nature Aging, 2021). These findings point to a common biology underlying cancer susceptibility, independent of specific genetic factors or breast cancer subtype.
In exploring the loss of cellular identity in luminal cells, we identified PEAK1 as a protein whose expression changes with age (iScience, 2021). Targeting the PEAK1 pathway pharmacologically led to the selective elimination of aged luminal cells. Our strategy aims to combine the identification of aging biomarkers to spot individuals at high risk for breast cancer with the use of targeted prevention methods based on our understanding of aging biology.
Delineating the role of microenvironment as an influential mediator of epithelial plasticity in normal and malignant human mammary epithelial cells
My research delves into epithelial plasticity in human cells, focusing on how both normal and cancerous adult human stem cells respond to their surrounding environment. Collaborating with Mina Bissell, a leading figure in the study of breast tumor environments and three-dimensional culture systems, and Rene Villadsen and Ole Petersen, we managed to isolate normal human mammary stem cells for the first time (Journal of Cell Biology, 2007). A significant challenge in studying human epithelial stem cells lies in the limitations of existing models to accurately replicate the stem cells' natural environments, making it difficult to dissect the influence of specific microenvironment components on stem cell behavior as can be done in model organisms.
To bridge this gap, I developed the microenvironment microarray (MEMA) technology, enabling the analysis of cell behavior across thousands of defined microenvironments (Integrative Biology, 2009). This platform was a cornerstone of the MEP-LINCs program with Joe Gray (U54HG008100), allowing us to show how different microenvironments can dictate the differentiation of human mammary progenitor cells (Cellular Signaling, 2024). In an extended collaboration with Jim Lorens at the University of Bergen, we explored the AXL receptor tyrosine kinase's role in mammary epithelia of humans and mice. We discovered that AXL is critical for sustaining multipotent progenitors and stem-like states in both species. Inhibiting AXL in mouse models effectively prevented tumor development (iScience, 2020), suggesting AXL's key role in managing cell plasticity.
We propose that under certain conditions, many cancer cells could act as cancer stem cells, driven by the AXL pathway's interaction with the tumor microenvironment. Indeed, we found that exposing breast cancer cells to specific tumor environment proteins induced AXL expression. This activation allowed the cells to tap into stem cell and epithelial-mesenchymal transition (EMT) gene programs, enhancing their resistance to chemotherapy (Frontiers, 2018). Furthermore, using MEMA, we demonstrated that cancer cells from the breast, prostate, and lung respond differently to the drug lapatinib based on the stiffness and composition of their microenvironments, highlighting a spectrum of drug-response phenotypes (Cell Reports, 2017). This research underscores the complex interplay between cancer cells and their microenvironment, paving the way for new therapeutic strategies that target this dynamic.
Mark LaBarge is a professor and stem cell biologist in the Department of Population Sciences at the Beckman Research Institute at City of Hope National Medical Center.
In addition to his scientific pursuits, Dr. LaBarge is Director of the Postdoctoral Training Office at City of Hope, and he is passionate about thoughtful mentorship in STEM and is trained as a facilitator by the Center for the Improvement of Mentored Experiences in Research.

Lab Members


Dr. Miyano is an expert in chromatin organization and molecular biology. His current project explores the roles of age-varied transcription factors in breast for use as biomarkers of cancer risk and potential therapeutic targets.


Ms. Lopez is an expert on primary human mammary epithelial cell culture and she is the backbone of the LaBarge Lab.


Dr. Hinz is a cell and molecular biologist focusing on understanding the consequences of age-dependent intermediate filament changes in human mammary epithelial cells. His current project mechano-node pore sensing and AI classification of biomechanical phenotypes to assess breast cancer risk.


Mr. Carlison is a PhD candidate whose dissertation work focuses on mechanisms of microenvironment-epithelial progenitor cell interactions in high-risk breast tissue.


Mr. Casano is developing a nascent project understanding the role of age-varied epigenetic regulators in breast cancer initiation.
The LaBarge Lab is always interested in recruiting top postdoctoral and graduate talent. Please send inquiries and CV to Mark LaBarge.
Lab Alumni
- Tara Fresques, Ph.D., NRSA F32 Postdoctoral Fellow, Assistant Professor, University of the Pacific
- Michael Todhunter, Ph.D., American Cancer Society Postdoctoral Fellow, Bioentrepreneur & co-Founder, Dragonase
- Arrianna (Zirbes) Carey, Ph.D. student, Medical Writer, Nucleus Global
- Fanny Pelissier-Vatter, Ph.D. student, Postdoc, Cornell University, now Sr. Scientist, FluoSphera
- ChunHan Lin, Ph.D. student, Software engineer, Linked-In
- Sundus Shalabi, M.D., Ph.D. student, Assistant Professor, Arab American University
- Lorena Mora-Blanco, Ph.D., Postdoctoral Fellow, CIRM Scholar, Associate Director and Principal Scientist R&D, Helix
- Rosalyn Sayaman, Ph.D., Postdoctoral Fellow, CMTP F31 Fellow, Professional Researcher in Computational Biology, K01 recipient, UC San Francisco
- Tiina Jokela, Ph.D., Staff Scientist, Marie Sklodowska-Curie Actions Research Fellow, University of Jyväskylä, Finland
- James Garbe, Ph.D., Research Scientist, Gartner Lab, UC San Francisco
- Klara Sputova, Research Associate, Plastic & Reconstructive Surgeon (specializing in breast reconstruction!), UT Health Houston
- Jonathan Lee, Research Associate, Sr. Manager, Fate Therapeutics
- Jessica Bloom, Research Associate, Ph.D. student, UC San Diego
- Sophie Girardin, MS student, EPFL, Business Development Manager, Bioengineer, SEED Biosciences
- Charlotte Broennemann, MS student, EPFL, Business Development Manager, Bioengineer, SEED Biosciences
Partnerships
We collaborate with organizations in progressing the development of new treatments in our specialized areas of research.

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Contact Information
34.1293487, -117.9726643
Duarte, CA 91010