Rab40b regulates MMP2 and MMP9 trafficking during invadopodia formation and breast cancer cell invasion

Abstract

SummaryInvadopodia-dependent degradation of the basement membrane plays a major role during metastasis of breast cancer cells. Basement membrane degradation is mediated by targeted secretion of various matrix metalloproteinases (MMPs). Specifically, MMP2 and MMP9 (MMP2/9) possess the ability to hydrolyze components of the basement membrane and regulate various aspects of tumor growth and metastasis. However, the membrane transport machinery that mediates targeting of MMP2/9 to the invadopodia during cancer cell invasion remains to be defined. Because Rab GTPases are key regulators of membrane transport, we screened a human Rab siRNA library and identified Rab40b GTPase as a protein required for secretion of MMP2/9. We also have shown that Rab40b functions during at least two distinct steps of MMP2/9 transport. Here, we demonstrate that Rab40b is required for MMP2/9 sorting into VAMP4-containing secretory vesicles. We also show that Rab40b regulates transport of MMP2/9 secretory vesicles during invadopodia formation and is required for invadopodia-dependent extracellular matrix degradation. Finally, we demonstrate that Rab40b is also required for breast cancer cell invasion in vitro. On the basis of these findings, we propose that Rab40b mediates trafficking of MMP2/9 during invadopodia formation and metastasis of breast cancer cells.

NanoVelcro-captured CTC number concomitant with enhanced serum levels of MMP7 and MMP9 enables accurate prediction of metastasis and poor prognosis in patients with lung adenocarcinoma

“…Additionally, CTC formation was reported to be facilitated by larger tumor size in many solid tumors. [23][24][25][26][27] However, there was no significant correlation between tumor size and CTC count in our results ( Figure 2D; Table 1). …”

The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion

“…1,5,33,34 Among these, the MMPs were shown to be the most functionally significant proteases associated with invadopodia activity in cancer cells. MMPs comprise a large family of zinc-dependent enzymes, both membrane-bound and soluble, 1 which are capable of cleaving multiple ECM proteins 35 . The membrane-bound form, MT1-MMP (or MMP14), was shown to be not just an invasion-promoting component, but also a master regulator of invadopodia development, 33,36 whose recruitment promotes invadopodia maturation.…”

“…34,37 Soluble MMP9 and MMP2 are secreted around invadopodia, and promote local ECM degradation. 16,[35][36][37][38][39][40][41] Blocking MMP activity by inhibitors, antibodies, or siRNA impairs invadopodia function and matrix degradation. 1,5 Furthermore, MMP inhibition also inhibits invadopodia formation, suggesting that MMPs regulate and fine-tune invadopodia function, at early stages of their formation.…”

Physical exercise modulates the level of serum MMP-2 and MMP-9 in patients with breast cancer

“…In particular, MMP-2 and -9 serum levels increase following exercise training that incorporates resistance-type exercise, as the mechanical stressors result in ECM remodeling (26). MMP-2 and -9 hydrolyze components of the basement membrane, and regulate tumor growth and metastasis (27). Activated MMP-2 is located in the protruding section of the cell-penetrating matrix.…”