Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer

Abstract

The metastatic progression of cancer remains a major issue in patient treatment. Yet, the molecular and cellular mechanisms underlying this process remains unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor prognosis histological form of digestive cancers, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies: MUC CRCs either display a conventional “apical-in” polarity or, more frequently, harbor an inverted “apical-out” topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFb and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, this apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients.

Inverted apicobasal polarity in health and disease

“…These clusters were originally called tumor spheres with inverted polarity (TSIP), even though apical-out polarity is typically a normal feature of cell clusters in suspension. For some individuals with cancer, however, clusters retrieved from non-adhesive substrates maintain their apical-out polarity even when placed in 3D physiological matrices, suggesting a genuine inverted apicobasal polarity phenotype ( Canet-Jourdan et al, 2022 ; Okuyama et al, 2016 ; Onuma et al, 2021 ; Zajac et al, 2018 ).…”

“…Inverted apicobasal polarity also affects tumor growth and treatment resistance. Primary colorectal cancer organoids with an inverted apical-out phenotype better survive chemotherapeutic treatment compared to normally polarized apical-in organoids ( Canet-Jourdan et al, 2022 ). This could be due to a reduced proliferation rate in TSIPs compared to apical-in organoids, making them less susceptible to anti-mitotic drugs ( Canet-Jourdan et al, 2022 ).…”

“…In epithelial cells, this means the outward-facing ECM-adjacent membranes are depleted of basolateral proteins and enriched in apical markers such as microvilli and apical polarity proteins (bottom right of figure). This is observed in cancerous aggregates called TSIP ( Canet-Jourdan et al, 2022 ; Zajac et al, 2018 ), and in established epithelia of individuals with MVID with additional TTC7A gene alteration ( Michaux et al, 2016 ). When embedded in physiological matrices, organoids derived from individuals affected by several monogenic diseases also show fully inverted polarity (top right of figure) ( Bigorgne et al, 2014 ; Li et al, 2022 ; Michaux et al, 2016 ).…”

Bioengineered 3D Ovarian Models as Paramount Technology for Female Health Management and Reproduction

“…Although such mechanism is not fully understood, loss or switch in the orientation of the apical-basal polarity of epithelial cells has been linked to cancer initiation and metastasis [85]. Interestingly, tumoroids are also able to invert their apical-basal polarity (apical-in or apical-out) [86,87], and could therefore be a suitable model to investigate mechanisms of metastasis. OC tumoroids embedded in hydrogel (in contact with ECM) have apical-in polarity; however, OC tumoroids cultured in suspension (ascites) show an apical-out polarity [88].…”

The molecular biology of peritoneal metastatic disease

“…Cluster formation is mediated by adhesion molecules such as integrin α v β 3 , which also confers resistance to anoikis (Dolinschek et al , 2021). Tumor cell clusters with an inverted apico‐basolateral polarity (apical side out) can be found in peritoneal effusions of patients with PMD and are associated with poor prognosis (Zajac et al , 2018; Canet‐Jourdan et al , 2022). These inverted structures could already be detected in the primary tumor, suggesting collective invasion as the mechanism of dissemination.…”