Rab35-dependent extracellular nanovesicles are required for induction of tumour supporting stroma

Area of Science:

• Cell Biology
• Cancer Research
• Nanotechnology

Background:

• Cell-to-microenvironment communication is vital in disease progression.
• Extracellular nanovesicles from cancer cells modulate the tumor microenvironment, promoting angiogenesis and metastasis.
• Understanding factors regulating nanovesicle secretion is key to cancer nano-communication.

Purpose of the Study:

• Investigate the roles of RAB11B and RAB35 in regulating nanovesicle secretion and their impact on cancer-stromal cell communication.
• Determine the specific nanovesicle populations regulated by RAB11B and RAB35.
• Assess the functional consequences of depleting these factors on tumor growth and microenvironment modulation.

Main Methods:

• Generated prostate cancer cells with stable knockdown of RAB11B and RAB35.
• Analyzed cell health, nanovesicle secretion, and communication with fibroblastic stromal cells.
• Utilized 3D in vitro models and in vivo xenografts for functional assessments.

Main Results:

• RAB11B and RAB35 regulate distinct nanovesicle populations, each comprising approximately 20% of the total.
• RAB35 depletion, unlike RAB11B depletion, resulted in nanovesicles unable to drive fibroblast to myofibroblast differentiation.
• RAB35 knockdown significantly attenuated tumor growth and myofibroblast presence in vivo, while RAB11B knockdown had minimal effect.

Conclusions:

• A RAB35-regulated nanovesicle subpopulation is critical for intercellular communication between cancer and stromal cells.
• This RAB35-dependent pathway is essential for establishing a tumor-supportive microenvironment.
• Targeting RAB35-mediated nanovesicle communication presents a potential therapeutic strategy in cancer.