{"id":1178,"date":"2025-01-25T20:18:40","date_gmt":"2025-01-25T20:18:40","guid":{"rendered":"https:\/\/staging.irccs.com\/?post_type=laboratory&p=1178"},"modified":"2025-12-24T11:30:29","modified_gmt":"2025-12-24T10:30:29","slug":"translational-cancer-medicine","status":"publish","type":"laboratory","link":"https:\/\/irccs.com\/it\/laboratori\/translational-cancer-medicine\/","title":{"rendered":"TRANSLATIONAL CANCER MEDICINE"},"content":{"rendered":"\n

<\/span>Research topic<\/h2>\n\n\n\n

Tumors adapt dynamically to therapeutic interventions, evolving mechanisms that defy static genomic profiling and limiting the utility of such snapshots for guiding treatment decisions. Current clinical research lacks tools to capture how therapies reshape regulatory circuits in tumors across time and space. Likewise, designing clinical trials that keep pace with the complexity and constant evolution of molecular data remains a formidable challenge. To address this gap, the Laboratory of Translational Cancer Medicine develops patient-derived models \u2013 including xenografts and tumoroids \u2013 that retain the biology and genetics of human cancers. These models provide an experimental platform to analyze complex variables and perform high-throughput studies. Focusing on colorectal cancer (CRC), our work seeks to elucidate the mechanisms of tumor evolution under drug pressure, identify predictive biomarkers of therapeutic response to optimize patient stratification, and uncover biological dependencies that may serve as actionable targets.<\/p>\n\n\n\n

<\/span>Background<\/h2>\n\n\n\n

Realizing the full promise of precision oncology requires platforms and datasets that capture the molecular diversity of tumors. Patient-derived xenografts (PDXs) \u2013 generated from surgical resections or biopsies engrafted and serially propagated in immunocompromised mice \u2013 and organotypic three-dimensional cultures (tumoroids) derived from patient samples serve as powerful tools to meet this need. Both preserve the dynamics of tumor evolution and can be propagated longitudinally in vivo or ex vivo. This enables the study of tumor heterogeneity and clonal adaptation, cancer stem cell hierarchy and plasticity, phylogenetic trajectories, and signaling and transcriptional dynamics at single-cell resolution. Importantly, PDXs and tumoroids recapitulate interpatient variability, offering a clinically relevant framework for biomarker discovery and the development of targeted therapies for molecularly defined subgroups.<\/p>\n\n\n\n

<\/span>Research achievements<\/h2>\n\n\n\n

Our research focuses on how tumors depend on oncogenic drivers and how this dependency is modified by genomic and functional factors, with an emphasis on CRC. We employ a comprehensive experimental pipeline that integrates multidimensional data analysis, preclinical validation in PDXs, and mechanistic investigation in matched tumoroids.<\/p>\n\n\n\n

The laboratory has pioneered the systematic use of PDXs and tumoroids to catalogue and functionally interrogate cancer genes, assessing their value as drug-response biomarkers and therapeutic targets. Through multidimensional analyses of large PDX cohorts, we contributed to refining CRC taxonomy by developing transcriptional classifiers with both prognostic and predictive utility. Using whole-genome sequencing of clonal tumoroids maintained in short- and long-term culture, we uncovered fundamental principles of tumor heterogeneity, heritability, and the progression-associated amplification of DNA mutational instability as hallmarks of CRC evolution.<\/p>\n\n\n\n

Our work has also led to discoveries with immediate clinical relevance. Notably, our identification of HER2 amplification as a mechanism of resistance to EGFR blockade provided the rationale for the HERACLES clinical trial. This study demonstrated encouraging results in heavily pre-treated HER2-positive patients, with response and disease-control rates that compared favorably with other therapies used in the same setting.<\/p>\n\n\n\n

We further investigated adaptive drug tolerance to EGFR inhibition in metastatic CRC, revealing pharmacologic strategies to enhance the depth of response to anti-EGFR therapy. These studies also uncovered lineage-based adaptive reprogramming as a mechanism by which cancer cells evade pathway dependency and therapeutic eradication.<\/p>\n\n\n\n

<\/span>Conclusions and perspectives<\/h2>\n\n\n\n

our studies establish a systematic framework for functionally evaluating anticancer therapy responses in human cancer. They reveal novel mechanisms underlying responsiveness to standard-of-care therapies and provide a refined molecular vocabulary for the rational management of CRC, with immediate translational and clinical implications.<\/p>\n\n\n\n

<\/span>Publications<\/h2>\n\n\n\n

At this link<\/a><\/strong>, you can find all the scientific publications of the Principal Investigator.<\/p>\n\n\n\t

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Selected Publications<\/h2>\n\t\t\t\t
\n\t\t\t\t\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\t\t\t\t\tThe molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer<\/a>\n\t\t\t\t\t\t\t\t\t\t\t\t

Avolio M, Leto SM, Sassi F, Lupo B, Grassi E, Catalano I, Zanella ER, Vurchio V, Cottino F, Tsantoulis PK, Lazzari L, Luraghi P, Ferri M, Galimi F, Berrino E, Bellomo SE, Viviani M, Sogari A, Mauri G, Tosi F, Cruciani F, Sartore-Bianchi A, Siena S, Borghi F, Torri V, \u00c9lez E, Tabernero J, Nieva M, Montagut C, Tarazona N, Cervantes A, Tejpar S, Bardelli A, Marchi\u00f2 C, Marsoni S, Bertotti A, Trusolino L. Cancer Discov. 2025 Sep 22. doi: 10.1158\/2159-8290.CD-24-0556.<\/p>\n\t\t\t\t\t<\/div>\n\t\t\t\t\t\t\t\t\t

\n\t\t\t\t\t\t\t\t\t\t\t\t\tThe genomic landscape of response to EGFR blockade in colorectal cancer. <\/a>\n\t\t\t\t\t\t\t\t\t\t\t\t

Bertotti A*, Papp E, Jones S, Adleff V, Anagnostou V, Lupo B, Sausen M, Phallen J, Hruban CA, Tokheim C, Niknafs N, Nesselbush M, Lytle K, Sassi F, Cottino F, Migliardi G, Zanella ER, Ribero D, Russolillo N, Mellano A, Muratore A, Paraluppi G, Salizzoni M, Marsoni S, Kragh M, Lantto J, Cassingena A, Li QK, Karchin R, Scharpf R, Sartore-Bianchi A, Siena S, Diaz LA Jr, Trusolino L*, Velculescu VE*. Nature 526:263-267 (2015).\r\n<\/p>\n\t\t\t\t\t<\/div>\n\t\t\t\t\t\t\t\t\t

\n\t\t\t\t\t\t\t\t\t\t\t\t\tHeterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer<\/a>\n\t\t\t\t\t\t\t\t\t\t\t\t

Grassi E, Vurchio V, Cresswell GD, Catalano I, Lupo B, Sassi F, Galimi F, Borgato S, Ferri M, Viviani M, Pompei S, Urgese G, Chen B, Zanella ER, Cottino F, Russo M, Mauri G, Pietrantonio F, Zampino MG, Lazzari L, Marsoni S, Bardelli A, Lagomarsino MC, Sottoriva A, Trusolino L, Bertotti A. Sci. Transl. Med. 2025;17:eado1641. <\/p>\n\t\t\t\t\t<\/div>\n\t\t\t\t\t\t\t\t\t

\n\t\t\t\t\t\t\t\t\t\t\t\t\tXENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients<\/a>\n\t\t\t\t\t\t\t\t\t\t\t\t

Leto SM, Grassi E, Avolio M, Vurchio V, Cottino F, Ferri M, Zanella ER, Borgato S, Corti G, di Blasio L, Somale D, Vara-Messler M, Galimi F, Sassi F, Lupo B, Catalano I, Pinnelli M, Viviani M, Sperti L, Mellano A, Ferrero A, Zingaretti CC, Puliafito A, Primo L, Bertotti A, Trusolino L. Nature Commun. 2024;15:7495<\/p>\n\t\t\t\t\t<\/div>\n\t\t\t\t\t\t\t\t\t

\n\t\t\t\t\t\t\t\t\t\t\t\t\tColorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell-like phenotype<\/a>\n\t\t\t\t\t\t\t\t\t\t\t\t

Lupo B, Sassi F, Pinnelli M, Galimi F, Zanella ER, Vurchio V, Migliardi G, Gagliardi PA, Puliafito A, Manganaro D, Luraghi P, Kragh M, Pedersen MW, Horak ID, Boccaccio C, Medico E, Primo L, Nichol D, Spiteri I, Heide T, Vatsiou A, Graham TA, \u00c9lez E, Argiles G, Nuciforo P, Sottoriva A, Dienstmann R, Pasini D, Grassi E, Isella C, Bertotti A, Trusolino L. Science Transl. 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