The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with A v B 3 integrin mediated by the disintegrin domain. Altered expression of A v B 3 integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and A v B 3 integrin might negatively modulate A v B 3 activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for A v B 3 integrin activation. Ablation of ADAM23 enhanced A v B 3 integrin activation by at least 2-to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic A v B 3 integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating A v B 3 integrin activation. [Cancer Res 2009;69(13):5546-52]

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Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy.

28 Background: The reorganization of cancer care delivery during the COVID pandemic had the potential to catalyze improvement in CWR adherence by reducing provision of low value care to minimize in-person visits and mitigate potential issues with staff and resource shortages. We evaluated the impact of COVID on adherence with CWR for supportive care, relevant to colorectal and anal cancer patients with stage IV disease at Princess Margaret Cancer Centre (PM) in Canada and AC Camargo Cancer Center (AC) in Brazil. Methods: Eligible patients had a new patient consult 02/2020- 12/2020 (COVID) or the same period in 2019 (control). Performance on individual CWR in the 6 months following initial consultation was calculated as the proportion of eligible patients meeting the recommendation. Results: The PM and AC cohorts each consisted of 100 patients; demographic and disease characteristics of COVID and control cohorts were similar within each centre. Marginally fewer patients received surgery during COVID (PM: 38.3 vs 49.1%, p = 0.28; AC: 54.8 vs 55.2%, p = 0.97). At PM, more patients received radiation therapy during COVID (36.2 vs 24.5%, p = 0.21), whereas the opposite occurred at AC (7.1 vs 17.2%, p = 0.14). A higher proportion of both PM and AC patients treated during COVID died within 6 months of initial consult than in 2019 (PM: 10.6 vs 7.5%, p = 0.015; AC: 21.4 vs 8.6%, p = 0.029). Adherence to selected CWR is summarized below; whereby a higher proportion means higher concordance with CWR. Conclusions: There was low overall adherence to CWR across both centers with no significant changes to patterns of care for patients with stage IV disease during the COVID-19 pandemic.[Table: see text]

Supplementary Figure 1 from ADAM23 Negatively Modulates α_vβ₃ Integrin Activation during Metastasis

Supplementary Figure 2 from ADAM23 Negatively Modulates α_vβ₃ Integrin Activation during Metastasis

Supplementary Table 1 from ADAM23 Negatively Modulates α_vβ₃ Integrin Activation during Metastasis