Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity

Abstract

Background Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance. Experimental design We generated a biobank consisting of 35 primary tumour regions and 59 paired PM from 12 patients. All samples were analysed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin. Results PM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumours belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitised PMDOs to a 1-h exposure to oxaliplatin, through increased platinum-DNA adduct formation. Conclusions These results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin.

Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging

“…Together the data indicate partial loss of epithelial identity and cell-cell contact in FAP-expressing tumour cells, but no clear gain in expression of mesenchymal genes, which is in line with a 'partial EMT' [31]. We recently demonstrated that peritoneal metastases from CRC constitute an almost homogeneous entity of CMS4 tumours [18,32]. Due to the small size of individual tumour nodules, the detection of peritoneal metastases by routine imaging is extremely challenging, hampering patient selection for surgery and assessment of treatment response [33,34].…”

“…In the accompanying paper [18], we have identified peritoneal metastases as a near-homogeneous CMS4 entity within CRC. The detection of peritoneal metastases in CRC is a major clinical challenge [33,34].…”

“…In this study, we have labelled the FAPI tracer on-site with 68 Ga. However, centralised production of 18 F-labelled FAPI would allow its distribution on a national or regional scale, which would contribute to widespread application and standardisation of CMS4 diagnosis.…”

“…Third, a composite cohort of more than 90 thousand single cells derived from 29 colorectal tumours and adjacent normal tissue with annotated cellular identities [17]. Fourth, a cohort of CRC primary tumour regions (n = 35) and paired peritoneal metastases (n = 59) [18]. Fifth, FFPE tissue from a cohort of colorectal liver metastasis patients (CRLM, n = 24) [5].…”

Detection of Experimental Colorectal Peritoneal Metastases by a Novel PDGFRβ-Targeting Nanobody

“…Recently, we performed an extensive molecular analysis of a cohort of colorectal peritoneal metastases and the primary tumours that give rise to them. We found that these tumours form a near-homogeneous entity of Consensus Molecular Subtype 4 (CMS4) [ 17 , 18 , 19 ], a subtype that is characterized by a high content of stromal myofibroblasts [ 20 , 21 , 22 ], which express high levels of FAP, but also Platelet-Derived Growth Factor Receptor alpha (PDGFRA) and Platelet-Derived Growth Factor Receptor beta (PDGFRB). Encouraged by the success of FAPI-PET [ 15 , 16 ], we set out to study the potential value of PDGFRB-targeted molecular imaging for the detection of peritoneal metastases and, potentially, other CMS4-like stroma-rich tumour types.…”