Driver gene KRAS aggravates cancer-associated stroke outcomes

Area of Science:

• Oncology
• Neurology
• Molecular Biology

Background:

• Cancer-associated stroke incidence is increasing due to improved cancer patient survival.
• The precise molecular mechanisms linking oncogenic mutations to stroke remain largely unknown.
• KRAS is a key driver gene frequently mutated across various cancer types.

Purpose of the Study:

• To investigate the role of KRAS mutations in cancer-associated ischemic stroke.
• To elucidate the molecular pathways involved in KRAS-driven stroke exacerbation.
• To assess the clinical impact of stroke in colorectal cancer patients with KRAS mutations.

Main Methods:

• Utilized a mouse model of ischemic stroke with KRAS-mutated (KRAS^G13D/-) and parental colorectal cancer cells.
• Performed neurological deficit assessments, tumor growth monitoring, and brain RNA sequencing.
• Analyzed serum cytokine levels, STAT3 phosphorylation, and patient prognosis data.

Main Results:

• KRAS^G13D/- cancer cells exacerbated neurological deficits post-stroke compared to parental cells.
• Stroke promoted tumor growth, an effect amplified by the KRAS^G13D/- allele.
• Increased pro-inflammatory chemokines/cytokines and STAT3 phosphorylation were observed in the KRAS^G13D/- group.
• STAT3 inhibition improved stroke outcomes by modulating microglia/macrophage polarization.
• Colorectal cancer patients with early stroke onset showed significantly worse prognosis.

Conclusions:

• KRAS mutations play a critical role in exacerbating ischemic stroke outcomes in cancer patients.
• An interplay exists between KRAS signaling, inflammation, and stroke severity.
• Targeting STAT3 may offer a therapeutic strategy for cancer-associated stroke.
• Early stroke occurrence is a negative prognostic indicator for colorectal cancer patients.