An Emerging Role of KRAS in Biogenesis, Cargo Sorting and Uptake of Cancer-Derived Extracellular Vesicles

Figures & data

Figure 1. Kirsten rat sarcoma virus-associated endosomal networking for extracellular vesicles biogenesis.

(A) Exposure to EGF promotes sorting of KRAS to early and late endosomes. (B) KRAS on the late endosomal membrane suppresses endosome-lysosome fusion and facilitates maturation of late endosome into MVBs to release small vesicles into the extracellular matrix. (C) KRAS promotes localization of Rab13, CD81 and EGFR at plasma membranes, resulting in release of Rab13⁺, CD81⁺, EGFR⁺ and CD63^- small EVs through membrane budding [33,35].

EVs: Extracellular vesicles; KRAS: Kirsten rat sarcoma virus protein; MVBs: Multivesicular bodies.

Figure 2. Carcinogenic properties of mutant Kirsten rat sarcoma virus cancer-derived extracellular vesicles.

EVs: Extracellular vesicles; KRAS: Kirsten rat sarcoma virus.

Figure 3. Mutant Kirsten rat sarcoma virus cancer-derived extracellular vesicles promote therapy resistance in recipient cells.

ATM: Ataxia-telangiectasia mutated; EVs: Extracellular vesicles; KRAS: Kirsten rat sarcoma virus; MRP1: Multidrug resistance-associated protein 1; MRP4: Multidrug resistance-associated protein 4; SLC3A2: Solute carrier family 3 member 2.

Figure 4. Effects of Kirsten rat sarcoma virus mutant cancer-derived extracellular vesicles on immune cells.

(A) Autophagy-dependent ferroptosis of KRAS^G12D mutant pancreatic cancer cells triggered the release of KRAS^G12D-containing EVs. (B) In recruited macrophages, ingested KRAS^G12D interacts with AGER receptors to promote M2-like TAM polarization. (C) KRAS^G12D colon cancer cells secrete EVs containing KRAS^G12D and IL-8 proteins as well as G-CSF into the TME. (D) Transfer of KRAS^G12D protein and IL-8 mRNA and protein elevates IL-8 expression in recruited neutrophils. (E) N2-like TAN polarization by G-CSF and upregulated IL-8 expression promote NET formation that facilitates angiogenesis, cancer migration, invasion and metastasis.

AGER: Advanced glycosylation end-product specific receptor; EVs: Extracellular vesicles; KRAS: Kirsten rat sarcoma virus; NET: Neutrophil extracellular trap; TAM: Tumor-associated macrophages; TAN: Tumor-associated neutrophils.

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