Breast Cancer Stem Cell-Derived ANXA6-Containing Exosomes Sustain Paclitaxel Resistance and Cancer Aggressiveness in Breast Cancer

Abstract

Continuous chemotherapy pressure-elicited annexin-A6 (ANXA6)-containing exosome (ANXA6-exo) secretion contributes to paclitaxel (PTX) resistance in breast cancer (BC), but the molecular mechanisms are not fully elucidated. The present study managed to investigate this issue and found that ANXA6-exo promoted PTX resistance and cancer progression in BC cells in a Yes-associated protein 1 (YAP1)-dependent manner. Specifically, the parental PTX-sensitive BC (PS-BC) cells were exposed to continuous low-dose PTX to generate PTX-resistant BC (PR-BC) cells, and we found that BC stem cells tended to be enriched in the descendent PR-BC cells in contrast with the PS-BC cells. In addition, PR-BC cell-derived exosomes were featured with highly expressed ANXA6, and ANXA6-exo delivered ANXA6 to promote cell migration, growth, autophagy, and stemness in PS-BC cells. Interestingly, ANXA6-exo increased PTX resistance in PS-BC cells via inducing autophagy, and the effects of ANXA6-exo on PTX resistance in PS-BC cells were abrogated by co-treating cells with the autophagy inhibitor 3-methyladenine. Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.

ANXA6: a key molecular player in cancer progression and drug resistance

“…Elevated ANXA6 has been proved to increase drug resistance by regulating autophagy in various tumors [ 46 , 93 , 94 ]. ANXA6-EVs induced by continuous chemotherapeutic pressure promotes drug resistance, cell migration, stemness, and autophagy in paclitaxel-sensitive breast cancer cells [ 95 ]. ANXA6-EVs up-regulate yes-associated protein (YAP) to promote dysregulation of the Hippo pathway, contributing to the development of tumor resistance to some extent.…”

“…ANXA6-EVs up-regulate yes-associated protein (YAP) to promote dysregulation of the Hippo pathway, contributing to the development of tumor resistance to some extent. In addition, silencing YAP could counteract the effects of ANXA6-EVs on paclitaxel resistance and cancer aggressiveness in bladder cancer cells [ 95 ]. In nasopharyngeal carcinoma, ANXA6 promotes protective autophagy by inhibiting the PI3K/AKT signaling pathway, thereby promoting radioresistance [ 94 ].…”

Advances in understanding the role and mechanisms of tumor stem cells in HER2-positive breast cancer treatment resistance (Review)

“…Doheny et al ( 68 ) reported that knockdown of SMO inhibited BCSC growth, suggesting that Hedgehog pathway inhibitors may be useful in BCSC-targeted therapy. In addition, further signal transduction pathways, including the Hippo ( 69 ), TGF-β ( 70 ), JAK2/STAT3 ( 71 ) and PI3K/AKT/mTOR ( 72 ) pathways, are closely associated with BCSCs through their effects on BC occurrence and progression.…”

Pathobiological functions and clinical implications of annexin dysregulation in human cancers

“…In breast cancer, ANXA6 present in exosomes from stem cells promoted paclitaxel resistance via YAP1 upregulation. ANXA6 also promoted cell migration, autophagy, cell growth and stem properties ( Guo et al, 2021 ). In addition, ANXA6 has been involved in resistance to EGFR-TKIs such as lapatinib in TNBC, where ANXA6 upregulation is part of an adaptive mechanism to acquire resistance ( Widatalla et al, 2019 ).…”