Aggressive cancers pose significant clinical challenges due to their high metastatic potential and poor prognosis. Genotoxic treatments such as chemotherapy and radiotherapy induce DNA damage, often leading to the formation of micronuclei—aberrant nuclear structures that mark genomic instability. When micronuclei rupture, their DNA is exposed to cytosolic sensors like cGAS, activating the cGAS-STING pathway and triggering innate immune responses. While this can stimulate anti-tumor immunity, aggressive cancer cells may exploit cGAS-STING signaling to enhance their survival and progression. Thus, targeting micronuclei or modulating this pathway could offer promising therapeutic strategies.
Micronuclei indicate cellular damage and are typically targeted for elimination. Autophagy, crucial for degrading damaged cellular components, may play a key role in removing micronuclei in aggressive cancer cells. Our studies reveal a high prevalence of cGAS-positive (ruptured) micronuclei and a constitutively active innate immune response in these cells. Despite the presence of autophagy-associated proteins (LC3, p62, ubiquitin) at micronucleus and near lysosomes, we observed that micronuclei are not fully resolved over time, implying that autophagy may be insufficient for complete degradation.
Groundbreaking research from our lab highlights the importance of the ESCRT-III machinery in maintaining nuclear envelope integrity, and that accumulation of ESCRT-III components can lead to micronuclear catastrophe. However, the roles of individual ESCRT-III components in micronuclear surveillance remain poorly defined. Here, we investigate CHMP7, an ESCRT-III component, in regulating micronuclear stability and autophagy. CHMP7 knockdown increases cGAS-positive micronuclei and enhances lysosomal proximity, suggesting a potential compensatory clearance mechanism. Autophagic flux analysis using Halo-based reporters indicates a mild increase in both bulk and selective autophagy in CHMP7-deficient cells.
Given that CHMP7 is frequently depleted in various cancers, our study aims to elucidate its role at the intersection of nuclear integrity, autophagy, and inflammation—uncovering novel therapeutic opportunities for aggressive cancers driven by unresolved DNA damage.