Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals

Abstract

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.

A disintegrin and metalloprotease 23 hypermethylation predicts decreased disease‐free survival in low‐risk breast cancer patients

“…Because we were unable to address ADAM23 methylation in the mesenchymal CTC subpopulation, we cannot exclude the possibility that differences in ADAM23 methylation in tumors of mesenchymal CTC‐positive and CTC‐negative patients could be associated with additional factors. In agreement with our hypothesis, Costa and coauthors showed in vitro and in vivo that ADAM23 intra‐allelic and intratumoral heterogeneity is critical for tumor growth and metastasis . They suppose that during metastatic progression, epigenetic instability may provide tumor cells with a growth advantage, leading to selection of clones with the densest methylation profiles .…”

“…They also showed that ADAM23 silencing can elicit a phenotypic switch from a proliferative to an invasive phenotype of tumor cells. Moreover, they showed that in ADAM23 heterotypic environments, cells without ADAM23 expression promote tumor growth and metastasis by enhancing the proliferation and invasivity of adjacent ADAM23‐positive cells …”

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

“…Addressing tumor microregional heterogeneity in time and space, the “multifaceted heterogeneity” of glioblastoma both between different tumors of similar H&E histology and within an individual tumor both in space and over time [3, 4]. A recent study of aggressive human breast cancers by Costa et al is exemplary of this phenomenon [5] that applies to glioblastoma. They demonstrated marked micro-regional heterogeneity within a single tumor mass with respect to a particular proteinase, ADAM-23, showing further that ADAM-23 positive and ADAM-23 negative subpopulations had different but mutually supporting functions [5].…”

“…A recent study of aggressive human breast cancers by Costa et al is exemplary of this phenomenon [5] that applies to glioblastoma. They demonstrated marked micro-regional heterogeneity within a single tumor mass with respect to a particular proteinase, ADAM-23, showing further that ADAM-23 positive and ADAM-23 negative subpopulations had different but mutually supporting functions [5]. Heterotypic environments create growth vigor in that ADAM-23 negative cells alone are invasion-competent but proliferation-poor while ADAM-23 positive subpopulations are proliferation-competent, invasion-weak [5].…”

“…They demonstrated marked micro-regional heterogeneity within a single tumor mass with respect to a particular proteinase, ADAM-23, showing further that ADAM-23 positive and ADAM-23 negative subpopulations had different but mutually supporting functions [5]. Heterotypic environments create growth vigor in that ADAM-23 negative cells alone are invasion-competent but proliferation-poor while ADAM-23 positive subpopulations are proliferation-competent, invasion-weak [5]. We look to this phenomenon of mutually reinforcing subpopulations with spatial and temporal intratumoral heterogeneity that is also unstable over time as a primary cause of previous chemotherapy failures.…”