PHLDA2
Phlda2 expression (red dots) in mouse placenta regions distinguished by color during placental development (Wu et al., 2024. Cell Discov). Phlda2 is highly expressed in the labyrinth of the placenta which is highlighted with a dotted line.
Metastasis and developmental biology
Breast cancer metastasis is the principal driver of breast cancer-related mortality with 5-year survival rates dropping steeply from 99% for localized disease to 32% after metastasis occurs. This underscores the urgent need to understand its fundamental mechanisms to identify new therapeutics targets. Accumulating evidence suggests that metastatic competency is not only acquired through random genetic mutations but often involves the aberrant reactivation of latent developmental programs normally confined to embryogenesis. Cancer cells can hijack these pathways, such as those governing angiogenesis and epithelial-mesenchymal transition (EMT), to gain critical migratory, invasive, and survival advantages. This process frequently involves dedifferentiation towards a more plastic, primitive state, resulting in the emergence of cancer cells possessing the unique self-renewal capacity required to seed and establish metastases. Elucidating how cancer cells to co-opt fundamental developmental blueprints represents a critical frontier in cancer research and holds significant promise for identifying novel therapeutic vulnerabilities.
PHLDA2 in placenta development and cancer
In previous work, we screened for cellular programs important for metastasis using single-cell RNA sequencing (Davis et al. 2020, Nat Cell Biol). This identified pleckstrin homology-like domain family A member 2 (PHLDA2) as a top gene upregulated in metastatic cells. PHLDA2 was first named Imprinted in Placenta and Liver (IPL) in the late 1990s when it was identified as a maternally expressed imprinted gene. To date, the function of PHLDA2 has been studied most extensively in placental development where it is expressed by trophoblasts. Trophoblasts drive formation of the feto-maternal interface (referred to as the labyrinth in mice), where exchange of oxygen and nutrients from mother to fetus occurs. Proper development of the labyrinth requires trophoblast invasion from the outer layer of the blastocyst and upregulation of vascular remodeling gene programs to support the formation of the labyrinth’s
matrix of blood vessels. Trophoblasts and cancer cells share striking similarities in their migratory capabilities and ability to promote angiogenesis, although trophoblasts maintain these processes under tight regulation unlike the uncontrolled nature of cancer cells. In breast cancer, increased PHLDA2 expression has been associated with poor prognosis, but its function and role in disease progression remain unclear.
PHLDA2 expression promotes vessel permeability or leakage in an in vitro vascular microtumor (VMT) system. Vascular permeability is highly correlated with metastatic spread thus suggesting a mechanism by which PHLDA2 enhances metastasis.
PHLDA2 promotes breast cancer metastasis by co-opting a developmental program for placental vascular remodeling
Identifying drivers of metastasis is essential for developing new treatments for patients with advanced disease. Here, we identify PHLDA2 as a robust driver of breast cancer metastasis. Previous work established PHLDA2 as an imprinted gene expressed by trophoblasts which are critical for vascular remodeling during placental development. We find that hypomethylation of PHLDA2 in breast tumors correlates with increased gene expression, which is associated with metastasis and poor survival in breast cancer patients. RNA-sequencing showed that PHLDA2 overexpression results in upregulation of genes that control invasion, extracellular matrix assembly, and vascular remodeling, consistent with trophoblast functions in placental development. Using an in vitro vascularized microtumor (VMT) system, we find that PHLDA2 functions through SPARC, which promotes metastasis by inducing vascular permeability and enhancing tumor dissemination. These data suggest that increased expression of PHLDA2 through hypomethylation promotes metastasis by ectopic expression of a developmental program for vascular remodeling.
Interactive analysis of PHLDA2 over expression dataset
