Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Bootsma, Sanne; Dings, Mark P.G.; Kesselaar, Job; Helderman, Roxan F.C.P.A.; van Megesen, Kyah; Constantinides, Alexander; Moreno, Leandro Ferreira; Stelloo, Ellen; Scutigliani, Enzo M.; Bokan, Bella; Torang, Arezo; van Hooff, Sander R.; Zwijnenburg, Danny A.; Wouters, Valérie M.; van de Vlasakker, Vincent C.J.; Galanos, Laskarina J.K.; Nijman, Lisanne E.; Logiantara, Adrian; Veenstra, Veronique L.; Schlingemann, Sophie; van Piggelen, Sterre; van der Wel, Nicole; Krawczyk, Przemek M.; Platteeuw, Johannes J.; Tuynman, Jurriaan B.; de Hingh, Ignace H.; Klomp, Jan P.G.; Oubrie, Arthur; Snaebjornsson, Petur; Medema, Jan Paul; Oei, Arlene L.; Kranenburg, Onno; Elbers, Clara C.; Lenos, Kristiaan J.; Vermeulen, Louis; Bijlsma, Maarten F.

doi:10.1016/j.xcrm.2024.101523

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PIPAC Pharmacologic and Clinical Data

Cortés‐Guiral,

Kranenburg,

Sgarbura

et al. 2024

Journal of Surgical Oncology

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Pressurized intraperitoneal aerosol chemotherapy (PIPAC) emerged as an innovative intraperitoneal chemotherapy delivery system to overcome the issue of limited efficacy of systemic therapies to induce response in peritoneal malignancies. Promising results for patients with mesothelioma peritonei and peritoneal metastasis from gastric, ovarian, colorectal, pancreatic, and hepatobiliary tumors origin are changing the landscape for patients otherwise just facing palliative treatment. Ongoing trials will shed more light on the actual benefits of PIPAC.

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PIPAC Pharmacologic and Clinical Data

Cortés‐Guiral,

Kranenburg,

Sgarbura

et al. 2024

Journal of Surgical Oncology

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Modelling oxaliplatin resistance in colorectal cancer reveals aSERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype

Wong,

Das,

Shirgaonkar

et al. 2024

Preprint

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Drug resistance and distant metastases are major contributors to mortality in colorectal cancer (CRC). Here we investigate mechanisms underlying acquired resistance to oxaliplatin, a first-line, standard-of-care CRC treatment. We generated oxaliplatin-resistant CRC tumor cells with clinically relevant dosing regimen, which displayed enhanced metastatic potential. Transcriptomic and phenotypic analyses revealed a critical function for cholesterol biogenesis in modulating TGFb signaling activity, which in turn regulates SERPINE1 expression, a gene we identified as a key player in promoting drug resistance and metastasis. Additionally, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that can predict overall and relapse-free survival (RFS) in clinical cohorts and is able to stratify patients into CMS4/iCMS3-fibrotic CRC subtypes, underscoring its clinical utility. Using mouse tumor models, we provide further evidence that targeting SERPINE1 and cholesterol biogenesis can be viable approaches to re-sensitize the resistant pro-metastatic CRC cells to oxaliplatin. This study not only elucidates the molecular underpinnings of drug resistance and metastasis in primary CRC, but also offers prognostic and therapeutic strategies to guide clinical management of the disease.

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Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Cited by 2 publications

References 48 publications

PIPAC Pharmacologic and Clinical Data

PIPAC Pharmacologic and Clinical Data

Modelling oxaliplatin resistance in colorectal cancer reveals aSERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype

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