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patient support and advocacy group, to its role as the major driving force for legislation and patient care,
and currently is a major advocacy force to promote CCM research. The annual international CCM research
conference, created and organized by Angioma Alliance, has become the largest CCM scientific meeting in
the world. In her article, Dr. Lee described how her organization has employed creative patient engagement
methods like subsidized genetic testing as well as targeting special/minority patient groups, such as patients
with CCM3 mutations, patients with the CCM1 Common Hispanic Mutation, and underserved African
American patients, to expand research participation and understanding of the pathogenesis , which will
[2]
provide instrumental information for future epidemiological CCM studies.

The article entitled “Molecular genetic analysis of cerebral cavernous malformations: an update” was
[3]
contributed by Ricci et al. , in which they provide an overall update on the current progress in the genetics
of CCMs, including the overall relationship of these three CCM genes and an updated listing of the CCM
mutations currently identified. They also evaluate the current strategies to examine the impact of the CCM
mutations on corresponding protein levels, and recapitulate the available data on penetrance, phenotype-
genotype correlations, and founder effects. Another review article entitled “Non-autonomous effects of
[4]
CCM genes loss”, authored by Finetti and Trabalzini , focuses on very recent advances in CCM genetic
studies, such as CCM onset and progression, loss of a CCM gene in a single cell scale in CCM lesions, and
clonal expansions. In a research article entitled “Furry is a component of the CCM3-GCKIII signaling
[5]
pathway”, Antwi-adjei et al. generated genetic mosaic Drosophila larvae and adults which are
heterozygous for the gene of interest (ccm3 or furry), and isolated homozygous mutant daughter cells for
their genetic experiments. They found that wing cells with mutant phenotypes for ccm3, or expressing
dominant negative GCKIII, produce identical wing hair defects as mutations in tricornered and furry,
which leads to their conclusion that CCM3 and GCKIII act upstream of Furry-Tricornered. They further
concluded that CCM3 is a novel component of this ancient kinase signaling cascade, based on the fact that
neither CCM1 nor CCM2 orthologs have been reported in flies . Finally, our group contributed a review
[6]
[5]
article, “Calm the raging hormone - a new therapeutic strategy involving progesterone-signaling for
hemorrhagic CCMs”, to summarize our recent discoveries that CCM signaling complex (CSC) modulates
progesterone-mediated actions between classic nuclear progesterone receptors (nPRs) and non-classic
membrane progesterone receptors (mPRs) in two nPR(+) (T47D, MCF7) and two nPR(-) (MDA-MB-231,
MDA-MB-468) breast cancer cells across three cancer research manuscripts . Furthermore, we also
[7-9]
demonstrated the impact of this signaling network on the maintenance of the Blood-Brain Barrier in
[10]
another vascular research manuscript . Last week in the 17th annual international CCM Scientific
Meeting, I surprisingly learned that there is an in-press clinical study that strongly supports our series of
experimental findings, and I am eager to read this new clinical outcome. In sum, the overall goal of this
special issue, as the title suggests, is to learn the successful lessons from the past, re-examine our current
data and research strategies for better research outcomes, and look towards the future glory of conquering
CCMs.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.