Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas

Zajac, Olivier; Raingeaud, Joël; Libanje, Fotine; Lefèbvre, Céline; Sabino, Dora; Martins, Isabelle; Roy, Pétronille; Benatar, Clara; Canet-Jourdan, Charlotte; Azorin, Paula; Polrot, Mélanie; Gonin, Patrick; Benbarche, Salima; Souquère, Sylvie; Pierron, Gérard; Nowak, Damien; Bigot, Ludovic; Ducreux, Michel; Malka, David; Lobry, Camille; Scoazec, Jean‐Yves; Eveno, Clarisse; Pocard, Marc; Perfettini, Jean-Luc; Élias, Dominique; Dartigues, Peggy; Goèré, Diane; Jaulin, Fanny

doi:10.1038/s41556-017-0027-6

Cited by 101 publications

(113 citation statements)

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“…Four days after recovery, we performed time‐lapse imaging during 48 h and stained for actin and ezrin at end point. CRC histotype assessment indicated that 2 out of 10 patients had mucinous CRC, correlating with the inverted apico‐basolateral polarity of the explants we observed ex vivo and consistent with our previous study (Zajac et al , ) (Figs EV2A and EV2B, patients #E and #H, excluded from the present study focusing on NOS adenocarcinomas). For all patients with adenocarcinoma (8/8), all tumour explants remained cohesive and most displayed one or multiple lumens (77.7 ± 6.3% and 81.6 ± 4.9% visualized by DIC or ezrin staining, respectively, Figs A and B, EV2C and D).…”

Section: Resultssupporting

confidence: 92%

“…We found that inhibition of ROCK triggers the formation of leaders and the transition from non‐invasive to protrusive cohorts that undergo collective invasion. This is in contradiction with the pro‐invasive role of ROCK identified in CIMP CRCs explants (Zajac et al , ), mice xenografted with cell lines (Itoh et al , ; Croft et al , ; Sadok et al , ) or transgenic models of pancreatic cancer (Rath et al , ). However, our results are in agreement with the recent large‐scale in vivo RNAi screen revealing that loss of Myosin‐II triggers the formation of invasive skin cancers (Schramek et al , ) and that expression of active ROCK2 increases proliferation, but not invasion in similar models (Samuel et al , ).…”

Section: Discussionmentioning

confidence: 88%

“…First, the histological type and/or the molecular background of cancer may influence invasion mode and ROCK function. In line with this, ROCK has an anti‐invasive role in NOS CRCs that mostly display chromosomal instability, and a pro‐invasive function in MUC CRCs that arise from the CIMP pathway of carcinogenesis (Zajac et al , ). In addition, crosstalk with specific oncogenes and tumour suppressors, such as KRAS, Smad4 or JAK1, can modify the expression level and activity of ROCK (Sahai et al , ; Hoogwater et al , ; Sanz‐Moreno et al , ; Voorneveld et al , ), yet we did not detect a significant correlation with KRAS status in our cohort (Fig EV2A).…”

Section: Discussionmentioning

confidence: 91%

“…Cancer cell clusters can also invade as cohesive groups, a process called collective invasion. First observed from primary tumour explants over 20 years ago (Friedl et al, 1995), the collective invasion of cancer cells has been confirmed over the past decade by intravital microscopy in a variety of experimental model systems (Friedl, 2004;Alexander et al, 2008;Giampieri et al, 2009) and the systematic prospective analysis of primary tumour explants (Zajac et al, 2018). Yet, the cellular and molecular mechanisms underlying this process have been poorly investigated and most of our knowledge is based on the collective migration driving the embryonic development of model organisms.…”

Section: Introductionmentioning

confidence: 95%

“…Tissue-specific GEFs control the polarized activation of either Rac1 or Cdc42 in leader cells in vitro and in vivo (Osmani et al, 2006(Osmani et al, , 2010Bianco et al, 2007;Migeotte et al, 2010;Wang et al, 2010;Ellenbroek et al, 2012;Cai et al, 2014;Omelchenko et al, 2014;Westcott et al, 2015;Yamaguchi et al, 2015). In contrast, the collective invasion of tumour spheres with inverted polarity (TSIPs) in hypermethylated colorectal carcinomas is independent of Rac1 and protruding leader cells (Zajac et al, 2018). In follower cells, the level of RhoA-GTP is tightly controlled at cell-cell contacts in order to relax the junctions while maintaining the communication and the cohesion of the group during the migration (Omelchenko & Hall, 2012;Omelchenko et al, 2014;Reffay et al, 2014;Zaritsky et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

et al. 2019

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The metastatic progression of cancer is a multi‐step process initiated by the local invasion of the peritumoral stroma. To identify the mechanisms underlying colorectal carcinoma (CRC) invasion, we collected live human primary cancer specimens at the time of surgery and monitored them ex vivo. This revealed that conventional adenocarcinomas undergo collective invasion while retaining their epithelial glandular architecture with an inward apical pole delineating a luminal cavity. To identify the underlying mechanisms, we used microscopy‐based assays on 3D organotypic cultures of Caco‐2 cysts as a model system. We performed two siRNA screens targeting Rho‐GTPases effectors and guanine nucleotide exchange factors. These screens revealed that ROCK2 inhibition triggers the initial leader/follower polarization of the CRC cell cohorts and induces collective invasion. We further identified FARP2 as the Rac1 GEF necessary for CRC collective invasion. However, FARP2 activation is not sufficient to trigger leader cell formation and the concomitant inhibition of Myosin‐II is required to induce invasion downstream of ROCK2 inhibition. Our results contrast with ROCK pro‐invasive function in other cancers, stressing that the molecular mechanism of metastatic spread likely depends on tumour types and invasion mode.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

et al. 2019

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Untangling the complexities of micropapillary cancer^†

Campbell

2021

The Journal of Pathology

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Distinct morphological subtypes of colorectal cancer (CRC) confer a bleak clinical outlook. In a recent issue of The Journal of Pathology, Onuma et al investigated morphological evolution of a highly fatal CRC subtype known as micropapillary cancer (MPC). This study enhances understanding of MPC biology including essential regulatory signals, cellular and multicellular phenotypes, as well as cancer behaviour. Iterative modelling in three-dimensional (3D) patient-derived CRC tissue-originated spheroids (CTOSs) revealed spatiotemporal oscillations of Rho-ROCK hyperactivity underlying reversal of membrane polarity and suppression of lumen formation during development of multicellular MPC morphology. Corroborative studies in CTOSs, xenografts, and archival human CRCs confirm human disease relevance. Although cancer morphology has previously been considered irreversible, targeted inhibition of Rho-ROCK activity restored membrane polarity, lumenized multicellular assembly, and suppressed MPC morphology in 3D CTOS cultures and xenografts. Collectively, the study identifies molecular, biophysical, and multicellular mechanisms implicated in morphological evolution of micropapillary CRC.

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Cell‐Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells

Zárubová

Hasani-Sadrabadi

Norris

et al. 2022

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The migration of cancer cell groups is highly dependent on the chemical and physical guidance cues provided by the tumor stroma, which polarize cell collectives and enable their coordinated movement. For example, macrophages attracted by cancer cells can stimulate the multicellular streaming of tumor cells. [7] Moreover, activated fibroblasts in tumor stroma exert forces on cancer cells [8] and create tracks [9] in extracellular matrix (ECM) or align collagen fibers, [10] which promote efficient directional migration of groups of cancer cells along these features. The movement of cohesive multicellular groups is generally led by an invasive leader cell, which creates a path and sets the direction of migration for non-invasive follower cells in the group. [11] Once the groups of cancer cells invade the vasculature, they can dynamically reorganize and adjust their geometries to pass even through narrow blood vessels. [12] These multicellular groups, also known as circulating tumor cell clusters (CTCCs), can contain between 4 -100 cells. [12] However, CTCCs found in the bloodstream of cancer patients are not composed solely of cancer cells and may also contain mesenchymal cells, endothelial cells, and/or immune cells. [13] Clusters of mesenchymal cells with cancer cells have been detected in the peripheral blood of patients with metastatic breast cancer but not in the blood of healthy donors. The presence of circulating CAFs in the blood was confirmed in 88% of patients with metastatic disease and only in 23% of patients with localized breast cancer. [14] Similarly, increased numbers of circulating mesenchymal cells correlated with a worse prognosis and a lower probability of survival in metastatic patients. [15] The importance of co-traveling mesenchymal/ stromal cells in the metastatic process is also supported by observations that up to 86% of carcinoma cells that spread to the lungs were accompanied by primary tumor stroma-derived cells; in the majority of cases, these cells stained positive for smooth muscle α-actin (α-SMA) but only 28% cases stained positive for F4/80, a macrophage marker. [16] When the tumor stromal cells were partially depleted, the number of metastases significantly decreased.While mesenchymal stromal cells (MSCs) are known to be recruited to damaged or inflamed tissue, where they promote tissue regeneration, MSCs are also attracted to tumor sites. [17][18][19] Currently, without lineage tracing experiments, it is difficult to Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of the collective cell migration phenomenon and the involvement of various cell types during this process is needed. Here, an in vitro platform based on inverted-pyramidal microwells to follow and quantify the collective migration of hundreds of tumor cell clusters at once is developed. These results indicate that mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the heterotypi...

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Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas

Cited by 101 publications

References 57 publications

ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

Untangling the complexities of micropapillary cancer^†

Cell‐Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells

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Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas

Cited by 101 publications

References 57 publications

ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

ROCK 2 inhibition triggers the collective invasion of colorectal adenocarcinomas

Untangling the complexities of micropapillary cancer†

Cell‐Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells

Contact Info

Product

Resources

About

Untangling the complexities of micropapillary cancer^†