Posted October 27, 2015
Sohail Tavazoie, M.D. Ph.D., The Rockefeller University
Tumor progression is often marked by cycles of tumor dormancy, prolonged periods of minimal or no cell growth. Dormancy of cancer cells is often due to a lack of signaling cues in the local microenvironment that promote cell proliferation. Eventually, through mechanisms not well understood, a subset of cancer cells can overcome these limitations and proliferate again. Greater understanding of the mechanisms of tumor dormancy and how cancer cells eventually overcome these roadblocks in the context of estrogen receptor- (ER)-negative breast cancer is the goal of research being performed by Dr. Sohail Tavazoie, supported by an FY12 Collaborative Scholars and Innovators Award in collaboration with Dr. Gregory Hannon.
To identify drivers of primary and metastatic tumor re-initiation, Dr. Tavazoie developed an in-vivo selection system for isolating subpopulations of ER-negative human breast cancer cells that have an enhanced tumor-forming ability. This method consists of injecting breast cancer cells at low cell numbers into the mammary fat pads of immunodeficient mice, followed by the generation of single-cell suspensions from the resulting tumors and re-injection over multiple rounds of serial dilution. Therefore, this protocol selects for cells that have an increased ability to initiate tumor formation rather than simply proliferating at the highest rate. Microarray analysis of the tumorigenic-enriched and highly metastatic sublines revealed that three genes (LAMA4, FOXQ1, and NAP1L3) were consistently overexpressed when compared with the parental cell populations. Jason Ross, a student in Dr. Tavazoie's lab further characterized the most abundantly overexpressed gene, LAMA4, and found that it promotes the re-initiation of tumors in the mammary gland and in other organ microenvironments. One important feature that drives cancer cell malignancy is the ability to proliferate in the absence of attachment to an underlying matrix, though the mechanisms for this are unknown. Expression of LAMA4 was found to contribute to this phenotype both in vitro and in vivo and requires β1-integrin for cell adhesion. Finally, in the context of breast cancer patients, LAMA4 expression was more highly expressed in malignant cancer cells relative to the adjacent pre-malignant cells and positively correlated with a decrease in relapse-free survival. Together, these results (published in May 2015 in the journal Nature Cell Biology) identify LAMA4 as a novel regulator of primary and metastatic ER-negative breast cancer re-initiation, which could serve as a potential therapeutic target in these patients.