Non-muscle Myosin II reactivation and cytoskeletal remodelling as a new vulnerability in therapy-resistant melanoma

Trabajo presentado en el 3rd ASEICA Educational Symposium, celebrado en modalidad virtual del 23 al 25 de noviembre de 2021.MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB may be driven by common transcriptomic alterations in pathways controlling invasion and metastasis. Using phosphoproteomic and transcriptomic analyses, we find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in levels in the ROCK-non-muscle Myosin II (NMII) pathway, which is essential for cancer invasion and metastasis. NMII activity is decreased shortly after MAPK is blocked. However, persister cells promptly restore NMII activity to increase survival, and this becomes a vulnerability, since survival of MAPKi- and ICB-resistant cells is highly dependent on ROCK-NMII. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species and unresolved DNA damage) and reducing myeloid- and lymphoid-driven immunosuppression, ultimately overcoming cross-resistance in vivo. In human tumours, high ROCK-NMII levels identify MAPKi-, ICB-resistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is more susceptible to ROCK-NMII blockade, suggesting clinical opportunities for combination therapies

The Myosin II cytoskeleton as a new vulnerability in therapy-resistant melanoma

Trabajo presentado en VIB Conference: Tumor Heterogeneity, Plasticity and Therapy, celebrado en modalidad virtual del 05 al 06 de mayo de 2021.MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB has been suggested to be driven, in part, by common transcriptomic alterations in pathways controlling invasion and metastasis. We find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in expression levels in the ROCK-Myosin II pathway, which plays a key role in cancer invasion and metastasis. Myosin II activity is decreased shortly after MAPK is blocked. However, resistant cells promptly restore Myosin II activity to increase survival, and this becomes a vulnerability, since survival of MAPKi- and ICB-resistant cells is highly dependent on ROCK-Myosin II. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species and unresolved DNA damage) and myeloid- and lymphoiddriven immunosuppression, overcoming cross-resistance. In human tumours, high ROCK-Myosin II activity and their associated transcriptome identify MAPKi-, ICBresistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is intrinsically more susceptible to ROCK-Myosin II inhibition, suggesting clinical opportunities for combination therapies

The Myosin II cytoskeleton as a new vulnerability in therapy-resistant melanoma

Trabajo presentado en el XIX Congreso de la Sociedad Española de Biología Celular, celebrado en Boadilla del Monte (España) del 26 al 29 de octubre de 2021.MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB has been suggested to be driven, in part, by common transcriptomic alterations in pathways controlling invasion and metastasis. We find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in expression levels in the ROCK-Myosin II pathway, which plays a key role in cancer invasion and metastasis. Myosin II activity is decreased shortly after MAPK is blocked. However, resistant cells promptly restore Myosin II activity to increase survival, and this becomes a vulnerability, since survival of MAPKi- and ICB-resistant cells is highly dependent on ROCK-Myosin II. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species, unresolved DNA damage and cell cycle arrest) and myeloid- and lymphoid-driven immunosuppression, ultimately overcoming cross-resistance. In human tumours, high ROCK-Myosin II activity and their associated transcriptome identify MAPKi-, ICB-resistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is intrinsically more susceptible to ROCK-Myosin II inhibition, suggesting clinical opportunities for combination therapies

The Myosin II cytoskeleton as a new vulnerability in therapy-resistant melanoma

Trabajo presentado en la EACR-AstraZeneca Virtual Conference ‘Drug Tolerant Persister Cells’, celebrada del 07 al 08 de diciembre de 2021.MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB may be driven by common transcriptomic alterations in pathways controlling invasion and metastasis. We find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in expression levels in the ROCK-non-muscle Myosin II (NMII) pathway, which is essential for cancer invasion and metastasis. NMII activity is decreased shortly after MAPK is blocked. However, persister cells promptly restore NMII activity to increase survival, and this becomes a vulnerability, since survival of MAPKi- and ICB-resistant cells is highly dependent on ROCK-NMII. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species and unresolved DNA damage) and reducing myeloid- and lymphoid-driven immunosuppression, ultimately overcoming cross-resistance. In human tumours, high ROCK-NMII levels identify MAPKi-, ICB-resistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is more susceptible to ROCK-NMII blockade, suggesting clinical opportunities for combination therapies

The non-muscle Myosin II cytoskeleton as a new vulnerability in therapy-resistant melanoma

Trabajo presentado en el 19th International Congress of the Society For Melanoma Research, celebrado en Edimburgo (Escocia) del 17 al 20 de octubre de 2022.MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB may be driven by common transcriptomic alterations in pathways controlling invasion and metastasis. We find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in expression levels in the ROCK-non-muscle Myosin II (NMII) pathway, which is essential for cancer invasion and metastasis. Persister cells overactivate NMII to increase survival, and this becomes a vulnerability, since survival of MAPKiand ICB-resistant cells is highly dependent on ROCK-NMII. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species and unresolved DNA damage) and reducing myeloid- and lymphoiddriven immunosuppression, ultimately overcoming cross-resistance. In human tumours, high ROCK-NMII levels identify MAPKi-, ICB-resistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is more susceptible to ROCK-NMII blockade, suggesting clinical opportunities for combination therapies

A Current Overview of Two Viroids That Infect Chrysanthemums: Chrysanthemum stunt viroid and Chrysanthemum chlorotic mottle viroid

The chrysanthemum (Dendranthema X grandiflorum) belongs to the family Asteraceae and it is one of the most popular flowers in the world. Viroids are the smallest known plant pathogens. They consist of a circular, single-stranded RNA, which does not encode a protein. Chrysanthemums are a common host for two different viroids, the Chrysanthemum stunt viroid (CSVd) and the Chrysanthemum chlorotic mottle viroid (CChMVd). These viroids are quite different from each other in structure and function. Here, we reviewed research associated with CSVd and CChMVd that covered disease symptoms, identification, host range, nucleotide sequences, phylogenetic relationships, structures, replication mechanisms, symptom determinants, detection methods, viroid elimination, and development of viroid resistant chrysanthemums, among other studies. We propose that the chrysanthemum and these two viroids represent convenient genetic resources for host–viroid interaction studies

Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance

Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors