Type Iγ phosphatidylinositol phosphate kinase dependent cell migration and invasion are dispensable for tumor metastasis.

Type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) has been associated with poor prognosis in breast cancer patients by promoting metastasis. Among the six alternative-splicing isoforms of PIPKIγ, PIPKIγ_i2 specifically targets to focal adhesions and regulates focal adhesion turnover, thus was proposed responsible for tumor metastasis. In the present study, we specifically depleted PIPKIγ_i2 from mouse triple negative breast cancer (TNBC) 4T1 cells and analyzed their behaviors. As expected, PIPKIγ_i2-depleted 4T1 cells exhibited reduced proliferation, migration, and invasion in vitro at a comparable level as pan-PIPKIγ depleted cells. However, PIPKIγ_i2 depletion had no effect on metastasis and progression of 4T1 tumors in vivo. PIPKIγ_i2-depleted tumors showed similar levels of growth, hypoxia state, macrophage infiltration, and angiogenesis as parental tumors, although the pan-PIPKIγ depletion led to substantial inhibition on these aspects. Further investigation revealed that depleting PIPKIγ_i2 alone, unlike depleting all PIPKIγ isoforms, had no effect on PD-L1 expression, the status of the epithelial-to-mesenchymal transition, and the anchorage-independent growth of 4T1 cells. In human TNBC MDA-MB-231 cells, we obtained similar results. Thus, while PIPKIγ_i2 indeed is required for cell migration and invasion, these characteristics are not decisive for metastasis. Other PIPKIγ isoform(s) that regulate the expression of key factors to support cell survival under stresses is more critical for the malignant progression of TNBCs.