Using the force : targeting p60AmotL2-mediated invasion in cancer

Mechanotransduction is the process by which cells convert mechanical forces into biochemical signals—and vice versa—thanks to a coordinated cascade of effects regulated by mechanomodulatory and cytoskeletal complexes. These complexes transduce force signals to and from the nucleus to elicit cellular adaptations in processes such as proliferation, division, differentiation, and migration.

AmotL2 is one of those mechanomodulatory proteins; it acts by forming a complex with cadherins, catenins and actin filaments in cell-cell junctions to transduce force signals to and from the nucleus and elicit a biological response. AmotL2 has been found to play a crucial role in many physiological processes, for instance, by regulating cell shape and organizing actin filaments during development and tissue homeostasis. More recently, AmotL2 has also been implicated in pathological processes—such as cancer invasion and metastasis— through the expression of a shorter isoform of AmotL2 under conditions of extreme hypoxia, termed p60AmotL2. Metastasis account for over 90% of cancer-related deaths, so finding treatments that specifically target invasive cancer cells is of the utmost importance to improve overall survival.

In our quest to understand the role of p60AmotL2 in cancer invasion, and how we could target it, our lab has recently uncovered that p60AmotL2 acts as a dominant-negative of p100AmotL2, uncoupling radial actin filaments and impairing force transduction from cell-cell junctions to and from the nucleus. This resulted in an increase in nuclear elasticity that allowed p60AmotL2-expressing cells to migrate through tight spaces and invade in a single-cell ameboid fashion.

Interestingly, we have also found that p60AmotL2 induces apical extrusion of individually-expressing cells during cell crowding events. However, neighboring cells were not able to induce extrusion when there were multiple adjacent cells expressing p60AmotL2. We posit that cancer cells might highjack this process in hypoxic conditions to bypass contact inhibition, leading to the formation of tumor masses that can then invade local and distant tissues.

To target p60AmotL2-mediated effects in cancer invasion, we have employed a high-throughput phenotypic drug screening approach to find compounds that specifically kill p60AmotL2-expressing cells. Based on the results presented in this thesis, we hypothesize that the activation of pro-invasive phenotypes during metastasis can expose vulnerabilities in nucleocytoskeletal and chromatin dynamics to be exploited by different cancer therapies, such as BET inhibitors or telomere-targeting agents like 6-thio-dG. Work is still ongoing in validating other lead compounds and understanding their mechanism of action in targeting invading cancer cells, with the goal of taking them from bench to bedside and improving patient outcomes.

List of scientific papers

I. Modulation of E-Cadherin Function through the AmotL2 Isoforms Promotes Ameboid Cell Invasion. Aravindh Subramani, Weiyingqi Cui, Yuanyuan Zhang, Tomas Friman, Zhihai Zhao, Wenmao Huang, Pedro Fonseca, Weng-Onn Lui, Vani Narayanan, Justyna Bobrowska, Małgorzata Lekka, Jie Yan, Daniel E Conway, Lars Holmgren. Cells. 2023 Jun 21;12(13):1682.
https://doi.org/10.3390/cells12131682

II. Deciphering the Role of p60AmotL2 in Epithelial Extrusion and Cell Detachment. Weiyingqi Cui, Aravindh Subramani, Pedro Fonseca, Yumeng Zhang, Le Tong, Yuanyuan Zhang, Lars Egevad, Andreas Lundqvist, Lars Holmgren. Cells. 2023 Aug 28;12(17):2158.
https://doi.org/10.3390/cells12172158

III. A phenotypic screening approach to target p60AmotL2-expressing invasive cancer cells. Pedro Fonseca, Weiyingqi Cui, Nona Struyf, Le Tong, Ayushi Chaurasiya, Felipe Casagrande, Honglei Zhao, Dinura Fernando, Xinsong Chen, Nicholas P. Tobin, Brinton Seashore-Ludlow, Andreas Lundqvist, Johan Hartman, Anita Göndör, Päivi Östling and Lars Holmgren. J Exp Clin Cancer Res. 2024. [Accepted]

IV. High-throughput screening for the identification of novel compounds that target p60AmotL2 invasive cancer cells. Pedro Fonseca, Francesco Massai, Hanna Axelson and Lars Holmgren. [Manuscript]