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M. Cecilia Caino, Ph.D.

Assistant Professor


Contact Information:

University of Colorado Denver
Department of Pharmacology
Mail Stop 8303, RC1-South
12801 East 17th Ave
Aurora CO 80045

Phone: (303) 724-3528
Fax: (303) 724-3663
Office: RC1-South, L18-6124

 
 

Affiliated Programs

Metastastic cancer remains incurable and invariably kills 90% of cancer patients. Despite significant progress in determining the molecular and biochemical determinants of the metastatic cascade, we still lack actionable targets for metastatic disease. Filling this gap, our lab focuses on understanding the importance of mitochondria biology in metastatic breast and prostate cancer.  Mitochondria are bioenergetic, biosynthetic, and signaling organelles that have been implicated in various aspects of tumorigenesis and therapy resistance.  Indeed, mitochondrial respiration has been linked to oncogene-dependent transformation, metabolic reprogramming, protein translation, tumor repopulation, cell motility and metastasis.  In this context, mitochondrial quality control mechanisms are emerging as drivers of metastasis and attractive therapeutic targets. 

 

Mitochondrial dynamics in cancer. A key mechanism by which tumors regulate mitochondrial functions are the collective processes of mitochondrial dynamics. Mitochondrial dynamics refers to spatiotemporal regulation of gross morphology, transport of organelles, inner membrane and cristae morphology, communication between adjacent mitochondria and contact with other organelles such as the endoplasmic reticulum. Tumor microenvironmental conditions (hypoxia, starvation and oxidative stress) exploit mitochondrial dynamics as adaptive mechanisms. In this context, the possibility that mitochondria trafficking might affect tumor biology is poorly studied. In a series of recent contributions, we show that tumor cells reposition mitochondria at subcellular sites of high energetic demands, thus powering up mechanisms of invasion and metastasis. Disparate stimuli, ranging from growth factor stimulation, to therapy resistance to hypoxic stress, led to the trafficking of energetically active mitochondria to the cortical cytoskeleton of tumor cells. In turn, regional energy production supported membrane lamellipodia dynamics and increased turnover of focal adhesion complexes.

Deregulated mitochondrial trafficking fuels metastasis. The mitochondrial trafficking machinery had been previously studied in the context of neuronal cells, and many of the molecules were believed to be neuron-specific.  Recently, we identified the molecular motors and adaptors responsible for trafficking of mitochondria in tumor cells by a genome-wide shRNA screen. Syntaphilin (SNPH), the molecular brake anchoring mitochondria to microtubules, is broadly expressed in normal tissues and lost in most cancer types, including breast cancer. Higher levels of SNPH were associated with removal of mitochondria from the cortical cytoskeleton, impaired focal adhesion dynamics and inhibition of tumor cell invasion and metastasis. In patients, SNPH loss in tumors correlated with shortened patient survival. Conversely, positive regulators of mitochondrial trafficking, the mitochondrial Rho GTPases (Miro) 1 and 2, were overexpressed in patient cohorts and were associated with poorer prognosis. Our current goal are: (i) to  dissect the molecular mechanisms underlying mitochondrial trafficking in tumors, particularly in the context of hypoxic stress from the tumor microenvironment; (ii) to understand how rewiring of the mitochondrial network in tumors impacts cellular behaviors that drive progressive and lethal cancer; and (iii) to examine the contribution of the mitochondrial trafficking components (SNPH, Miro1/2 and Kinesin) to tumor cell invasion and metastatic dissemination. ​ 

 

 Current Lab Members

 
 Results From Personnel : Selected site and subsites
First NameLast NameMiddle InitialDegreePosition
MitchellEllinwood BSCU Cancer Center Fellow
MadisonFurnish BSGraduate Student
VictoriaGenther BS/MSProfessional Research Assistant


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Selected publications

1.       Caino MC, Seo JH, Wang Y, Rivadeneira DB, Gabrilovich DI, Kim ET, Weeraratna AT, Languino LR, Altieri DC.  “Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer”. J Clin Invest. 2017 in press.

2.       Caino MC, Seo JH, Aguinaldo A, Wait E, Bryant KG, Kossenkov AV, Hayden JE, Vaira V, Morotti A, Ferrero S, Bosari S, Gabrilovich DI, Languino LR, Cohen AR, Altieri DC. “A neuronal network of mitochondrial dynamics regulates metastasis”. Nat Commun 2016 7, 13730 doi: 10.1038/ncomms13730. PMID: 27991488. PMCID: PMC5187409

3.       Caino MC and Altieri DC. “Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy”. Clin Cancer Res. 2016 Feb 1;22(3):540-5. doi: 10.1158/1078-0432.CCR-15-0460. PMID: 26660517. PMCID: PMC4738153

4.       Caino MC and Altieri DC. “Disabling mitochondrial reprogramming in cancer”. Pharmacol Res 2015 Sep 10. pii: S1043-6618(15)00201-7. doi: 10.1016/j.phrs.2015.08.022. PMID: 26365877. PMCID: PMC4684442

5.       Caino MC and Altieri DC. “Cancer cells exploit adaptive mitochondrial dynamics to increase tumor cell invasion”. Cell Cycle 2015;14(20):3242-7. doi: 10.1080/15384101.2015.1084448. PMID: 26317663. PMCID: PMC4825634

6.       Caino MC, Ghosh JC, Chae YC, Vaira V, Rivadeneira DB, Faversani A, Rampini P, Kossenkov AV, Aird KM, Zhang R, Webster MR, Weeraratna AT, Bosari S, Languino LR, Altieri DC. et al. “PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion”. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8638-43. PMID: 26124089. PMCID: PMC4507184

7.       Caino MC, Chae YC, Vaira V, Ferrero S, Nosotti M, Martin NM, Weeraratna A, O’Connell M, Jernigan D, Fatatis A, Languino LR, Bosari S, Altieri DC. “Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells”. J Clin Invest. 2013 Jul;123(7):2907-20. PMID:23921130. PMCID: PMC3998961.

8.       Chae YC, Caino MC, Lisanti S, Ghosh JC, Dohi T, Danial NN, Villanueva J, Ferrero S, Vaira V, Santambrogio L, Bosari S, Languino LR, Herlyn M, Altieri DC. “Control of tumor bioenergetics and survival stress signaling by mitochondrial Hsp90s”. Cancer Cell. 2012 Sep 11;22(3):331-44. PMID:22975376. PMCID: PMC3615709

9.       Caino MC, Lopez-Haber C, Kim J, Mochly-Rosen D, Kazanietz MG. “Proteins kinase Cɛ is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes”. Oncogene. 2012 May 17;31(20):2593-600. PMCID: PMC3432976.