Mechanisms of metastatic colorectal cancer

Despite extensive research and improvements in understanding colorectal cancer (CRC), its metastatic form continues to pose a substantial challenge, primarily owing to limited therapeutic options and a poor prognosis. This Review addresses the emerging focus on metastatic CRC (mCRC), which has historically been under-studied compared with primary CRC despite its lethality. We delve into two crucial aspects: the molecular and cellular determinants facilitating CRC metastasis and the principles guiding the evolution of metastatic disease. Initially, we examine the genetic alterations integral to CRC metastasis, connecting them to clinically marked characteristics of advanced CRC. Subsequently, we scrutinize the role of cellular heterogeneity and plasticity in metastatic spread and therapy resistance. Finally, we explore how the tumour microenvironment influences metastatic disease, emphasizing the effect of stromal gene programmes and the immune context. The ongoing research in these fields holds immense importance, as its future implications are projected to revolutionize the treatment of patients with mCRC, hopefully offering a promising outlook for their survival. Metastatic colorectal cancer (mCRC) has a poor prognosis, and therapeutic options are limited. This Review provides a comprehensive overview of the genetic and molecular underpinnings of mCRC, discussing the therapeutic potential arising from this knowledge. Despite metastatic disease being the main cause of death in colorectal cancer (CRC), its molecular basis remains poorly characterized, which hinders the development of therapeutic strategies.Data support the view that most driver events necessary for metastatic dissemination are acquired early during cancer evolution; however, mutations in oncogenes and tumour suppressor genes influence metastatic disease progression.Tumour cell plasticity is pervasive and necessary for metastatic progression; tumour cells co-opt different cell states during metastatic dissemination, relapse, outgrowth and therapy resistance.Metastases show either an immune-excluded or an immune-desert phenotype, implying a major role of the immune system in shaping metastatic CRC; different metastases from the same patient might exhibit distinct immune environments.A holistic view of immune evasion mechanisms in metastases is lacking, and emerging evidence suggests that metastases of different organs co-opt distinct tumour microenvironments and respond differently to immune therapies.