Background

Colorectal cancer (CRC) is the fourth cause of cancer-associated death worldwide, being the metastatic disease the principal cause of mortality. After surgical resection of primary CRC tumors, up to 40% of patients develop metastasis. Peritoneal metastasis is the most common metastatic manifestation of CRC, after liver metastasis, and in up to 25% of patients, the peritoneum is the unique site of metastasis. Patients with peritoneal tumor metastasis have a poor prognosis and suffer from excruciating symptoms, and severe incurable pain syndromes in their terminal stages of disease. Current therapeutical strategies for patients with peritoneal tumor metastasis, based on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, are suitable for a minority of patients, and have severe adverse effects and low efficacy. Therefore, alternative treatments to prevent CRC peritoneal metastatic growth remain an unmet medical need.

Since peritoneal macrophages fulfill a tumor growth promoting function, immunotherapeutical treatments against CRC peritoneal metastasis should pursue to revert peritoneal macrophage protumorigenic functions, and to this end, an in-depth knowledge of the function of peritoneal macrophages during CRC peritoneal metastatic tumor growth is needed.

Approach

In this context, current research in Carlos Ardavin’s lab aims to explore the origin, kinetics and induction of protumor functions of peritoneal macrophages during peritoneal CRC tumor metastasis. To this end, we have developed a mouse model of CRC peritoneal metastasis, based on the intraperitoneal injection of mouse tumor organoids, derived from primary tumors arising in genetically engineered mice, bearing mutations in Apc, Kras, Tgfbr2 and Trp53, and developing human-like metastatic CRC tumor growth, that were generated in Dr. Eduard Batlle’s lab (IRB, Barcelona). Our experimental program relies on vivo imaging (IVIS), whole mount immunofluorescence, confocal microscopy, flow cytometry, proteome profiler mouse cytokine arrays, cell biology and biochemistry techniques and RNAseq-based transcriptomic profiling.

Recent findings

Our data support that the low inflammatory status of the peritoneal cavity associated to CRC peritoneal tumor growth, restrained monocyte recruitment and formation of monocyte-derived non-resident macrophages, while enabling a marked cell proliferation-driven expansion of resident peritoneal macrophages. Tumor-induced Tim4⁺ TREM1+ resident peritoneal macrophages displayed a migratory and protumor transcriptomic signature, involving the activation of genes encoding important pro-tumorigenic molecules and potential targets for immunotherapy, such as A2A/A2B, ARG1, IRG1, PD-L1/2, SPP1 or TREM1. Correspondingly, during peritoneal CRC tumor growth, Tim4⁺ TREM1⁺ resident peritoneal macrophages migrated to the omentum, the main peritoneal target organ for peritoneal metastasis, and promoted CRC peritoneal tumor progression.