Previous work
Colorectal adenocarcinoma neoplasic glands undergo collective invasion
In order to identify signaling pathways triggering collective invasion from non-invasive neoplastic Colorectal carcinoma glands, we performed a siRNA screen in 3D organotypic cultures, targeting the RhoGTPases effectors as this signaling pathway controls all mode of cell locomotion.
Although in single cells and/or 2D culture, ROCK is associated with pro-migratory/invasion function, our results revealed an opposite role of this kinase in collective invasion from 3D CRC models.
Our results show that inhibition of ROCK activity promotes, in part, acto-myosin relaxation and Rac-1 activation through FARP2, inducing leader cell formation and collective invasion. Importantly enough, we demonstrated that tumor cells are not pre-programmed for leader function, but that changes in the actin organization is sufficient to promote their appearance and induce collective invasion from quiescent structures.
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ROCK2 inhibition triggers the collective invasion of colorectal carcinomas through the Guanine nucleotide Exchange Factor FARP2
Investigate CRC metastatic dissemination to the peritoneal microenviroment
Olivier Zajac, Joel Raingeaud, Fotine Libanje, Celine Lefebvre, Dora Sabino, Isabelle Martins, Pétronille Roy, Clara Benatar, Charlotte Canet-Jourdan, Paula Azorin, Mélanie Polrot, Patrick Gonin, Salima Benbarche, Sylvie Souquere, Gerard Pierron, Damien Nowak, Ludovic Bigot, Michel Ducreux, David Malka, Camille Lobry, Jean-Yves Scoazec, Clarisse Eveno, Marc Pocard, Jean-Luc Perfettini, Dominique Elias, Peggy Dartigues, Diane Goéré & Fanny Jaulin
The most frequent and abundant tumor intermediates found in the peritoneal effusion of CRC patients are spherical clusters of hundreds cells displaying an inverted A/B polarity, the apical pole surrounding the sphere periphery. These structures have never been described and we have named them TSIPs (Tumor Spheres with Inverted Polarity).
TSIPs form by the budding of cell collectives toward the apical pole of neoplastic epithelia (and not by aggregation or proliferation of single cells). We have named it “collective apical budding”. Cell-cell interactions supported by the multicellular environment provide indispensable survival signal to mucinous CRC cells, in suspension and in tissues.
TSIPs are invasive and exclusively undergo collective invasion in match patient peritoneum explants. They use a unique mode of collective invasion, independent of the adhesion to the ECM but relying on the contractility of the peripheral apical actomyosin cortex.
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Tumour Spheres with Inverted Polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas
Organoids as preclinical models to improve intraperitoneal chemotherapy effectiveness for colorectal cancer patients with peritoneal metastases
P.Roy, C.Canet-Jourdan, M.Annereau, O.Zajac, M.Gelli, S.Broutin, L.Mercier, A.Paci, F.Lemare, M.Ducreux, D.Elias, D.Malka, V.Boige, D.Goéré, F.Jaulin
Colorectal carcinoma patients with peritoneal carcinomatosis are mostly resistant to systemic chemotherapies and have to undergo a very heavy procedure based on a complete cytoreductive surgery combined with intraperitoneal chemotherapy. However, the benefice of this short hyperthermic contact chemotherapy during the surgery procedure is debated.
We have shown that,
(1) intraperitoneal chemotherapy is more efficient than intravenous delivery;
(2) the limited drug incubation time imposed by the surgery procedure do not provide any ways to improve the treatment, and
(3) Uncoupling surgery and chemotherapy open significant ways to improve chemotherapy efficiency, such as repeated cycles oxaliplatin.
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