Ilio Vitale

Genomic instability and dysregulated RNA processing are each recognized as core hallmarks of cancer, but accumulating evidence indicates that they are mechanistically intertwined rather than independent features. Chromosomal instability, mismatch-repair deficiency, and homologous recombination deficiency can reshape RNA splicing, 3′ end formation, and RNA surveillance through changes in gene dosage, DNA damage signaling, and alterations in regulatory elements. Conversely, aberrant splicing, polyadenylation, and RNA modifications can impair DNA repair, perturb mitotic control, and promote replication stress, thereby reinforcing genomic instability. This bidirectional circuit drives clinically relevant phenotypes, including therapeutic resistance, immune modulation, and emergent vulnerabilities that are not captured by DNA-centric biomarkers alone. Here, we present a unified framework for the genome instability–RNA processing axis and its direct clinical implications for cancer diagnosis, treatment stratification, and therapeutic exploitation, highlighting the most actionable mechanistic interfaces and discussing how integrated DNA-RNA biomarkers and rational combination strategies could extend precision oncology beyond static genomic lesions.

Therapeutic adaptive responses and secondary resistance represent major obstacles to effective colorectal cancer treatment. These dynamic adaptations arise within a permissive tumor microenvironment that sustains cancer cell survival, epithelial-mesenchymal plasticity and the outgrowth of drug-tolerant clones, ultimately driving disease progression and poor patient outcomes. Here, it is shown that AMC303, a highly selective CD44v6 inhibitor, needs to be combined with a PI3K/mTOR inhibitor to prevent or reverse anti-tumor therapeutic resistance and disease progression under tumor microenvironmental cues. Cytokines released by tumor-associated cells, such as HGF, induce c-Met phosphorylation, CD44v6 expression and enhanced clonogenicity, thereby expanding cancer stem cell populations that undergo transcriptional reprogramming towards a hybrid EMT state with increased resistance and metastatic potential. In colorectal cancer stem cell mouse avatars, HGF promotes phenotypic reprogramming even when canonical CD44v6/c-Met signaling is blocked by AMC303, acting instead through c-Met co-receptors and downstream PI3K/AKT and MAPK pathways. By suppressing compensatory PI3K/AKT and MAPK signaling, the addition of Apitolisib, the dual PI3K/mTOR inhibitor, reduces the proliferation rate and makes cancer cells more vulnerable to the in vitro exposure with standard chemotherapeutic regimen. Collectively, these findings support a therapeutic strategy that targets key molecular mechanisms underlying cancer cell reprogramming, adaptive therapeutic escape and the emergence of aggressive colorectal cancer phenotypes.

Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators, as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks. Such alterations (i.e., methylation, acetylation, and ubiquitination) are catalyzed by an array of dedicated enzymes with antagonistic activity, including methyltransferases and demethylases, acetyltransferases and deacetylases, as well as ubiquitin ligases and deubiquitinating enzymes. The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues. In line with this notion, epigenetic defects have been associated with a variety of human disorders, including (but not limited to) congenital conditions as well as multiple hematological and solid tumors. Here, we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness, i.e., the ability of a small population of poorly differentiated malignant cells to (1) self-renew while generating a more differentiated progeny, and (2) exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress. Moreover, we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.