Schaider, H. | bioRxiv Science

bioRxiv2022

Aspirin synergizes with regorafenib to reduce growth of colorectal cancer

PurposeRegorafenib is a multi-kinase inhibitor approved for refractory metastatic colorectal cancer. Previous studies have suggested that combining kinase inhibitors with aspirin may improve patient outcomes. We aimed to determine the effects of aspirin and regorafenib combination treatment in preclinical models of colorectal cancer. Experimental DesignSW480, RKO and LIM1215 colorectal cancer cell lines were treated with aspirin and regorafenib to determine effects on proliferation and cytotoxicity. RNA sequencing and Western blotting were performed to explore underlying molecular effects. Aspirin and regorafenib combination treatment was also tested using organoids derived from three human colorectal cancer tissue specimens. For the in vivo study, SW480-derived tumors were established in athymic mice. Tumor volume was measured during treatment with aspirin and regorafenib, followed by immunohistochemical staining for markers of proliferation and apoptosis. ResultsAspirin and regorafenib synergistically inhibited proliferation of colorectal cancer cell lines and patient-derived organoids, irrespective of KRAS or BRAF mutation status. This was associated with inhibition of the PI3K-Akt-mTOR pathway and activation of the AMPK pathway. Aspirin and regorafenib effectively inhibited growth of microsatellite stable KRAS-mutant SW480-derived tumors in vivo. Immunohistochemical staining for Ki67 and cleaved caspase 3 showed that combination treatment elicited a synergistic anti-proliferative effect, in addition to a pro-apoptotic effect that was driven by regorafenib. ConclusionsAspirin and regorafenib demonstrate synergistic anti-proliferative effects in preclinical models of colorectal cancer. This suggests that combining regorafenib with aspirin may be an improved treatment strategy for patients with refractory metastatic colorectal cancer.

cancer biology↗

bioRxiv2020

Functional melanoma cell heterogeneity is regulated by MITF-dependent cell-matrix interactions

Phenotypic heterogeneity of cancer cells plays a critical role in shaping treatment response. This type of heterogeneity is organized spatially with specific phenotypes, such as sharply demarcated clusters of proliferating and cell cycle-arrested cells, predominating within discrete domains within a tumor. What determines the occurrence of specific tumor cell phenotypes in distinct microdomains of solid cancers is poorly understood. Here, we show that in melanoma spatial organization of phenotypic heterogeneity is dictated by the expression and activity of MITF. We reveal that this lineage survival oncogene controls ECM composition and organization, and ROCK-driven mechanotransduction through focal adhesion maturation and actin cytoskeleton functionality. In turn, altered tumor microarchitecture and structural integrity impact tumor solid stress which then mediates phenotypic heterogeneity through p27Kip1. Rho-ROCK-myosin signaling is necessary to transmit the effect of the reciprocal cell-ECM regulation into phenotypic heterogeneity. Our findings place cell-ECM crosstalk as a central driver of phenotypic tumor heterogeneity. SignificancePhenotypic heterogeneity is a major culprit of cancer therapy failure. We demonstrate that phenotypic heterogeneity is controlled through tumor cell-ECM crosstalk resulting in altered tumor microarchitecture, mechanotransduction and Rho-ROCK-myosin signaling. Melanoma shares these physical properties with any solid cancer underscoring the importance of our findings for therapeutically targeting this phenomenon.

cancer biology↗