In solid tumours, such as melanoma, cancer cells crosstalk with their tumour microenvironment (TME) composed of the extracellular matrix (ECM) and a variety of non-neoplastic cells. This process influences survival, proliferation, and dissemination of cancer cells. Undoubtedly, this aspect is crucial for a more accurate and complete understanding of cancer and its management.
Part I: We demonstrate that melanoma cell plasticity is dictated by the expression and activity of the lineage-survival oncogene MITF by controlling TME composition and organization and reducing ROCK-driven mechanotransduction. The resulting structural relaxation results in decreased p27Kip1 expression, ultimately reducing cell plasticity. Selective inhibition of ROCK phenocopies the effect of MITF. Our findings place tumour-TME crosstalk as a central driver of melanoma cell plasticity. We propose that reducing melanoma cell plasticity will benefit targeted therapy, while structural relaxation and decreased tumour solid stress will improve immune checkpoint therapy.
Part II: We show that the microtubule plus-end tracking proteins (+TIPs) CLASP1 and CLASP2 are essential for melanoma invasion into the tumour stroma. ‘Normal’ melanoma cells readily invade into the stroma by squeezing through its complex ECM, while CLASP-depleted cells cannot withstand the shear forces of the stroma, consequently they rupture and die due to nuclear damage. We revealed that ‘normal’ melanoma cells are resistant to this physical stress, as they form a microtubule-dependent mechanoprotective mechanism: a flexible nuclear cage that protects the nucleus from shear forces. This nuclear cage is dependent on CLASP1 and CLASP2. We propose targeting CLASP1 and/or CLASP2 as a ‘migrastatic’ to prevent metastasis.
Part III: Immunogenic cell death (ICD) constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. The proteasome inhibitor bortezomib can elicit bona fide ICD, as demonstrated in malignant myeloma and mantle cell lymphoma, but not yet in melanoma. We show that bortezomib induces ER stress and apoptosis, enhances ICD markers (DAMPs) in vitro and is immunogenic in vivo. Bortezomib-induced ICD is a good strategy to recruit the inflammatory immune response. Bortezomib-induced ICD enhances response to immune checkpoint inhibitors, even in ICI-resistant tumours. We propose intralesional injection of bortezomib combined with systemic immune checkpoint inhibition to melanoma therapy.