Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 variant

Veronica Veschi, Laura R Mangiapane, Annalisa Nicotra, Simone Di Franco, Emanuela Scavo, Tiziana Apuzzo, Davide S Sardina, Micol Fiori, Antonina Benfante, Maria L Colorito, Gianfranco Cocorullo, Felice Giuliante, Calogero Cipolla, Giuseppe Pistone, Maria Rita Bongiorno, Aroldo Rizzo, Courtney M Tate, Xiaohua Wu, Scott Rowlinson, Louis F StancatoMatilde Todaro, Ruggero De Maria, Giorgio Stassi

Research output: Contribution to journalArticle

Abstract

Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.

Original languageEnglish
Pages (from-to)987-1003
Number of pages17
JournalOncogene
Volume39
Issue number5
DOIs
Publication statusPublished - Jan 2020

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    Veschi, V., Mangiapane, L. R., Nicotra, A., Di Franco, S., Scavo, E., Apuzzo, T., Sardina, D. S., Fiori, M., Benfante, A., Colorito, M. L., Cocorullo, G., Giuliante, F., Cipolla, C., Pistone, G., Bongiorno, M. R., Rizzo, A., Tate, C. M., Wu, X., Rowlinson, S., ... Stassi, G. (2020). Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 variant. Oncogene, 39(5), 987-1003. https://doi.org/10.1038/s41388-019-1047-4