Everardo Macias

Overview:

The overarching goal of the Macias lab is to gain basic mechanistic insights into clinically relevant actionable molecular targets with the eventual goal of aiding to reduce prostate cancer-specific mortality.

Our group integrates human cancer genomic data, functional genomic loss of function screens and pre-clinical in vitro and in vivo mouse models in order to identify, prioritize and validate potential therapeutic targets. Recently, we conducted a functional genomic kinome screen in obese and calorie restricted mice that identified various orphan kinases that are essential for tumor growth in an obese and lean host environment. We are steadily adapting drug development discovery capabilities and lead compound optimization strategies for increased target engagement, efficacy and drug like properties via collaboration with medicinal chemists and structural biologists. In parallel, we are conducting basic mechanistic studies to determine the mechanism of action, including live cell imaging phenotypic gain and loss of function genetic studies and various omic approaches.

Positions:

Assistant Professor in Pathology

Pathology
School of Medicine

Assistant Research Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

North Carolina State University

Grants:

Genetic screen of calorie restricted and western diet essential kinases in prostate cancer

Administered By
Pathology
Awarded By
Prostate Cancer Foundation
Role
Principal Investigator
Start Date
End Date

Targeting Ribosomal Biogenesis in Prostate Cancer

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Prostate Cancer and Obesogenic Factors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Characterization of NYP Peptides in Prostate Cancer

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Targeting NUAK2 to mitigate obesity-enhanced prostate cancer growth and metastasis

Administered By
Pathology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Publications:

Cyclin-dependent kinase 4 expression alters the number of keratinocyte stem cells in the mouse hair follicle.

Hair follicles regenerate periodically by spontaneously undergoing cycles of growth, regression, and relative quiescence. During the hair cycle, follicle stem cells residing in a specialized niche remain quiescent, and they are stimulated to proliferate throughout the growth phase of the hair follicle. Although cell cycle regulators play a prominent role during the activation of hair follicle stem cells, the identity and the role of these regulators have not been confirmed. Herein, we reported that stem cells located in the bulge region of the HF (BuSCs) express high levels of cyclin-dependent kinase 4 (CDK4) through the quiescent phase of the hair cycle. Using gain- and loss-of-function studies, we have determined that the CDK4 protein level affects the number of BuSCs. Transgenic expression of CDK4 in the bulge region of the hair follicles reduces the number of BuSCs, whereas CDK4 ablation resulted in an increasing number of BuSCs. These results suggest that deregulation of CDK4 protein levels contributes to distorting the self-renewal/proliferation balance and, in turn, altering the number of BuSCs.
Authors
Kim, SH; Rodriguez, LRL; Macias, E; Rodriguez-Puebla, ML
MLA Citation
Kim, Sun Hye, et al. “Cyclin-dependent kinase 4 expression alters the number of keratinocyte stem cells in the mouse hair follicle.Cell Biol Int, vol. 46, no. 5, May 2022, pp. 737–46. Pubmed, doi:10.1002/cbin.11765.
URI
https://scholars.duke.edu/individual/pub1507151
PMID
35032143
Source
pubmed
Published In
Cell Biol Int
Volume
46
Published Date
Start Page
737
End Page
746
DOI
10.1002/cbin.11765

MESH1 knockdown triggers proliferation arrest through TAZ repression.

All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of "alarmone" (p)ppGpp to arrest proliferation and reprogram transcriptome. While mammalian genomes encode MESH1-the homolog of the (p)ppGpp hydrolase SpoT, current knowledge about its function remains limited. We found MESH1 expression tended to be higher in tumors and associated with poor patient outcomes. Consistently, MESH1 knockdown robustly inhibited proliferation, depleted dNTPs, reduced tumor sphere formation, and retarded xenograft growth. These antitumor phenotypes associated with MESH1 knockdown were accompanied by a significantly altered transcriptome, including the repressed expression of TAZ, a HIPPO coactivator, and proliferative gene. Importantly, TAZ restoration mitigated many anti-growth phenotypes of MESH1 knockdown, including proliferation arrest, reduced sphere formation, tumor growth inhibition, dNTP depletion, and transcriptional changes. Furthermore, TAZ repression was associated with the histone hypo-acetylation at TAZ regulatory loci due to the induction of epigenetic repressors HDAC5 and AHRR. Together, MESH1 knockdown in human cells altered the genome-wide transcriptional patterns and arrested proliferation that mimicked the bacterial stringent response through the epigenetic repression of TAZ expression.
Authors
Sun, T; Ding, C-KC; Zhang, Y; Zhang, Y; Lin, C-C; Wu, J; Setayeshpour, Y; Coggins, S; Shepard, C; Macias, E; Kim, B; Zhou, P; Gordân, R; Chi, J-T
MLA Citation
Sun, Tianai, et al. “MESH1 knockdown triggers proliferation arrest through TAZ repression.Cell Death Dis, vol. 13, no. 3, Mar. 2022, p. 221. Pubmed, doi:10.1038/s41419-022-04663-6.
URI
https://scholars.duke.edu/individual/pub1512788
PMID
35273140
Source
pubmed
Published In
Cell Death & Disease
Volume
13
Published Date
Start Page
221
DOI
10.1038/s41419-022-04663-6

NUAK family kinase 2 is a novel therapeutic target for prostate cancer.

Current advancements in prostate cancer (PC) therapies have been successful in slowing PC progression and increasing life expectancy; however, there is still no curative treatment for advanced metastatic castration resistant PC (mCRPC). Most treatment options target the androgen receptor, to which many PCs eventually develop resistance. Thus, there is a dire need to identify and validate new molecular targets for treating PC. We found NUAK family kinase 2 (NUAK2) expression is elevated in PC and mCRPC versus normal tissue, and expression correlates with an increased risk of metastasis. Given this observation and because NUAK2, as a kinase, is actionable, we evaluated the potential of NUAK2 as a molecular target for PC. NUAK2 is a stress response kinase that also plays a role in activation of the YAP cotranscriptional oncogene. Combining pharmacological and genetic methods for modulating NUAK2, we found that targeting NUAK2 in vitro leads to reduction in proliferation, three-dimensional tumor spheroid growth, and matrigel invasion of PC cells. Differential gene expression analysis of PC cells treated NUAK2 small molecule inhibitor HTH-02-006 demonstrated that NUAK2 inhibition results in downregulation of E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition. In a syngeneic allograft model and in radical prostatectomy patient derived explants, NUAK2 inhibition slowed tumor growth and proliferation rates. Mechanistically, HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels. Our results suggest that NUAK2 represents a novel actionable molecular target for PC that warrants further exploration.
Authors
Fu, W; Zhao, MT; Driver, LM; Schirmer, AU; Yin, Q; You, S; Freedland, SJ; DiGiovanni, J; Drewry, DH; Macias, E
MLA Citation
Fu, Weiwei, et al. “NUAK family kinase 2 is a novel therapeutic target for prostate cancer.Mol Carcinog, vol. 61, no. 3, Mar. 2022, pp. 334–45. Pubmed, doi:10.1002/mc.23374.
URI
https://scholars.duke.edu/individual/pub1502358
PMID
34818445
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
61
Published Date
Start Page
334
End Page
345
DOI
10.1002/mc.23374

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.
Authors
Schirmer, AU; Driver, LM; Zhao, MT; Wells, CI; Pickett, JE; O'Bryne, SN; Eduful, BJ; Yang, X; Howard, L; You, S; Devi, GR; DiGiovanni, J; Freedland, SJ; Chi, J-T; Drewry, DH; Macias, E
MLA Citation
Schirmer, Amelia U., et al. “Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.Mol Ther, vol. 30, no. 1, Jan. 2022, pp. 485–500. Pubmed, doi:10.1016/j.ymthe.2021.08.029.
URI
https://scholars.duke.edu/individual/pub1494995
PMID
34450249
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Volume
30
Published Date
Start Page
485
End Page
500
DOI
10.1016/j.ymthe.2021.08.029

NUAK2 inhibition for prostate cancer.

Authors
Fu, W; Zhao, M; Schirmer, A; Maravilla, EJ; Yoon, J; You, S; Freedland, SJ; Macias, E
MLA Citation
Fu, Weiwei, et al. “NUAK2 inhibition for prostate cancer.Molecular Cancer Research, vol. 18, no. 8, 2020, pp. 46–46.
URI
https://scholars.duke.edu/individual/pub1457301
Source
wos-lite
Published In
Molecular Cancer Research : Mcr
Volume
18
Published Date
Start Page
46
End Page
46