Biology subjects

Ittmann, M. M.

Publications and source records attributed to Ittmann, M. M..

5 recordsLinked to original sources

bioRxiv2023

Role of Adenosine Deaminase in Prostate Cancer Progression

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African American (AA) men when compared to European-American (EA) men. PCa tends to be a highly heterogeneous malignancy with a complex biology that is not fully understood. We use metabolomics as a tool to understand the mechanisms behind PCa progression and disparities in its clinical outcome. A key enzyme in the purine metabolic pathway, Adenosine deaminase (ADA) was found upregulated in PCa. ADA was also associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio which is a surrogate for ADA activity was high in the urine of PCa patients and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in the expression of ADA during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis reveals that this tumor growth could be driven by the activation of mTOR signaling. Chronic ADA overexpression shows alterations in the cells adhesion machinery and a decrease in the adhesion potential of the cells to the extracellular matrix in vitro. Loss of cell-matrix interaction is critical for metastatic dissemination, suggestive of ADAs role in promoting metastasis. This is consistent with the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.

cancer biology↗

bioRxiv2022

Ultra-long-acting refillable nanofluidic implant confers full protection against SHIV infection in non-human primates

The impact of pre-exposure prophylaxis (PrEP) on slowing the global human immunodeficiency virus (HIV) epidemic hinges on effective drugs and delivery platforms. Oral regimens have represented the pillar of HIV PrEP for years. However, variable adherence has spurred development of long-acting delivery systems, which also aim at increasing PrEP access, uptake and persistence. Here we present an ultra-long-acting and transcutaneously refillable subcutaneous nanofluidic implant for constant and sustained release of islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, for HIV PrEP. In rhesus macaques, the ISL-eluting implants (nISL) achieved constant plasma ISL levels (median 3.14 nM) and peripheral blood mononuclear cells (PBMCs) ISL-triphosphate levels (ISL-TP) (median 0.16 pmol/106 cells) for over 20 months uninterrupted. These drug concentrations are above the established PrEP protection threshold. In two non-blinded, placebo-controlled studies with repeated low-dose rectal and vaginal SHIVSF162P3 challenges in male and female rhesus macaques, respectively, nISL implants conferred 100% protection against infection (p=0.0005 and 0.0009, respectively between nISL and placebo control groups). The nISL implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month period. Overall, our refillable nISL implant is a promising ultra-long-acting delivery technology for HIV PrEP. One Sentence SummaryAn ultra-long-acting and subcutaneous refillable nanofluidic implant achieved preventive levels of islatravir in non-human primates for 20 months without refilling and conferred 100% protection against rectal and vaginal SHIV transmission.

bioengineering↗

bioRxiv2022

Adipose triglyceride lipase is regulated by CAMKK2-AMPK signaling and drives advanced prostate cancer

Lipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered on de novo lipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Patient-derived phosphoproteomics identified adipose triglyceride lipase (ATGL), a previously suspected tumor suppressor, as a CAMKK2-AMPK signaling target that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL increased its lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and mass spectrometry imaging demonstrated ATGLs profound regulation of lipid metabolism in vitro and in vivo, remodeling membrane composition. Inhibition of ATGL induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as potential therapeutic targets for the treatment of CRPC and provide insights for future combination therapies.

cancer biology↗

bioRxiv2022

Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice: Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer

Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2s effects on whole body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of Camkk2 slows, but does not stop, primary prostate tumorigenesis in the TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) genetic mouse model. Consistent with prior epidemiological reports supporting a link between obesity and prostate cancer aggressiveness, TRAMP mice fed a high-fat diet exhibited a pronounced increase in the colonization of lung metastases. We demonstrated that this effect on metastatic spread was dependent on CAMKK2. Notably, diet-induced lung metastases exhibited a highly aggressive neuroendocrine phenotype. Concurrently, Camkk2 deletion improved insulin sensitivity in the same mice. Histological analyses revealed that cancer cells were smaller in the TRAMP;Camkk2-/- mice compared to TRAMP;Camkk2+/+ controls. Given the differences in circulating insulin levels, a known regulator of cell growth, we hypothesized that systemic CAMKK2 could promote prostate cancer cell growth and disease progression in part through cancer cell-extrinsic mechanisms. Accordingly, host deletion of Camkk2 impaired the growth of syngeneic murine prostate tumors in vivo, confirming nonautonomous roles for CAMKK2 in prostate cancer. Cancer cell size and mTOR signaling was diminished in tumors propagated in Camkk2-null mice. Together, these data indicate that, in addition to cancer cell-intrinsic roles, CAMKK2 promotes prostate cancer progression via tumor-extrinsic mechanisms. Further, we propose that CAMKK2 inhibition may also help combat common metabolic comorbidities in men with advanced prostate cancer.

cancer biology↗

bioRxiv2020

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling

Previous work has suggested androgen receptor (AR) signaling mediates cancer progression in part through the modulation of autophagy. Accordingly, we demonstrate that chloroquine, an inhibitor of autophagy, can inhibit tumor growth in preclinical mouse models of castration-resistant prostate cancer (CRPC). However, clinical trials testing chloroquine derivatives in men with CRPC have yet to yield promising results, potentially due to side effects. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular (inducible overexpression and shRNA-mediated knockdown), genetic (CRISPR/Cas9), and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5-AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1). These findings are consistent with data indicating CAMKK2-AMPK-ULK1 signaling correlates with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Finally, we demonstrate that, similar to CAMKK2 inhibition, a recently described inhibitor of AMPK-ULK1 signaling blocked autophagy, cell growth and colony formation in prostate cancer cells. Taken together, our findings converge to demonstrate that AR signaling can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Further, we propose that an inhibitor of this signaling cascade could serve as an alternative, more specific therapeutic compared to existing inhibitors of autophagy that, to date, have demonstrated limited efficacy in clinical trials due to their toxicity and poor pharmacokinetics.

cancer biology↗