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Epigenetic evolution of colorectal cancer and its microenvironment reveals new vulnerabilities

Livanova, A.; Azzolin, L.; Cambuli, F.; Chemi, F.; James, C.; Ferrazzano, A.; Rusconi, F.; D'Agosto, S.; Mulas, I.; Randon, G.; Prisciandaro, M.; Raimondi, A.; Ghelardi, F.; Ambrosini, M.; Manca, P.; Palermo, F.; Niger, M.; Sottotetti, E.; Martinetti, A.; Maspero, M.; Sposito, C.; Ferrari, P.; Lamparelli, L.; Bautista, D.; Ricciardelli, E.; Simeoni, F.; Rotta, L.; Peano, C.; Mazzaferro, V.; Graham, T.; Pietrantonio, F.; Sottoriva, A.

2026-08-11 cancer biology
10.64898/2026.08.10.743840 bioRxiv
Show abstract

Epigenetics is central to tumorigenesis, but the co-evolution of the cancer epigenome and its microenvironment is severely understudied. Here, we measure chromatin accessibility and transcriptome, at single cell resolution, of a set of normal colon, primary colorectal cancers and metastases, and identify recurrent epigenetic alterations in tumour cells. We also found that the normal epithelium adjacent to the cancer had recurrent epigenetic alterations associated with inflammatory programs that were partially shared with tumour cells. Distinct tumour-intrinsic transcription factor binding programs were associated with differential abundance of malignant stroma cell identities. We then leveraged matched patient-derived organoids, to assess the functional impact of the most recurrent epigenetic alterations on cancer cell viability, using CRISPR interference. We found a set of epigenetic-driven cancer dependencies, related to developmental reprogramming and cellular stress resilience, representing new potential therapeutic targets.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.