Press: Mitochondrial Inhibitors Against Prostate Cancer

Newsday Report on our Research with Metformin Type Drugs
Top Stories, April 23rd, 2018

Exciting article on the state of prostate cancer therapy with Metformin and our quest to better understand and improve it.

We are working with urologists at Northwell Health to define a set of measurables to precisely monitor if the drug is doing to the cancer cells what we found it is supposed to do. This is critical to find out when and how the drug should be taken and if there are new drugs that perform better.

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Publication: Mitochondrial Inhibitors Against Prostate Cancer

Complex I inhibitors can selectively kill PTEN-null Cells
Adam Naguib & Grinu Mathew, 2/ 2018

A drug screen revealed that PTEN-null cells are highly vulnerable to mitochondrial complex I inhibition under conditions in which Pten-WT cells remain perfectly viable. Such an approach could serve as a blueprint for selective targeting of lethal PTEN-deficient metastatic prostate cancer. This is of high relevance to men who take the complex I inhibitor Metformin, a very popular anti-diabetic drug. A specific requirement for selective kill is limiting of glucose. PTEN-null cells respond to the inhibitors by increasing glucose consumption and importing ATP into their mitochondria, as Grinu could demonstrate. This effectively converts mitochondria from energy producers to energy consumers and results in an energy crisis that PTEN-wt cells do not encounter.

How could we now help the many men with prostate cancer that take Metformin?
We are working with urologists at Northwell Health to define a set of measurables to precisely monitor if the drug is doing to the cancer cells what we found it is supposed to do. This is critical to find out when and how the drug should be taken and if there are new drugs that perform better.

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CSHL Press Release

 

Postdoc News:

Dawid starts his own lab at Cornell Medical, 2/2018

Dawid has started his position as Assistant Professor of Pharmacology in Medicine at Weill Cornell Medical College. We wish him and his family all the best in their new home!

Nowak Lab Website

Publication: The Achilles' Heel of PTEN

Nuclear Import receptor of PTEN protects from cancer -
Muhan Chen & Dawid Nowak, 2/ 2017

Low PTEN protein levels are a driver of many cancer types. How is this achieved? PTEN levels are stabilized by a failsafe: once ubiuitinated PTEN esacpes the cytoplasmic degradation machinery by nuclear import. But when the nuclear import receptor is lost, the failsafe breaks down. Here Muhan and Dawid define the nuclear import receptor of PTEN: Importin 11. They show that its loss results in lung and prostate cancer with low PTEN in mouse. In pateints, loss of Importin 11 protein independently predicts lung cancer stage and correlates with low PTEN protein. Thus, the gene locus of Importin 11, IPO11 at 5q12, could be an independent marker for PTEN protein status and disease progression.

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CSHL Press Release

 

Publication: High Fat Diet and PTEN-deficient Prostate Cancer

High Fat Diet accelerates prostate cancer -
with David Labbé & Michel Tremblay, McGill University, 3/ 2016

High Fat diet does not appear to affect PTEN-deficient prostate cancer in mice. However when the PTP1B phosphatase is also lost there is increased cancer formation. PTP1B is involved in controlling Diabetes. This positions it at the crucial intersection of diet and cancer control.

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Publication: Eavesdropping on Metastasis

Immune signaling accelerates prostate metastasis -
Dawid Nowak, 6/ 2015

Proggressive accumulation of alterations in DNA are the driving force in progression from indolent to metastatic, life threatening prostate cancer. However, it remains challenging to monitor these alterations in patients because they happen inside the cell nucleus. Therefore, Dawid asked in this study if DNA alterations that trigger metastasis can be monitored outside the cell. He found that Interleukin 6 (IL6) secretion by metastasizing prostate cancer cells is critical to sustain their proliferation after they lose the PTEN and p53 anti-cancer genes. It became clear that these cells both secrete and then take up the secreted IL6 to activate STAT3 and MYC, known drivers of metastasis. It remains to be seen if this secretion also is intended to communicate with the environment and promote processes such as colonization of a metastatic site. Importantly, Dawid and the RapidCaP team could identify mice that harbored the malignant tumor cells by detecting secreted IL6 in the blood. We hope to use this assay in our effort to define signature events that reveal the transition to life-threatening prostate cancer.

CSHL Press Release

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Publication: PTEN Functions on Endocytic Vesicles

Cancer signals are packaged, then presented to PTEN
Adam Naguib, 4/ 2015

The majority of PTEN is localized throughout the cytoplasm. Using superresolution microscopy on endogenous PTEN we show that microtubules organize PTEN localization because it attaches to vesicles. This localization is critical for PTEN function as we identify the motif on PTEN that mediates the vesicle binding. When mutated, PTEN is inactive in cells, but it can be reactivated by fusion to a vesicle targeting domain. Surprisingly, the vesicle binding domain of PTEN is found repeated in the Auxilin proteins, which mediate an essential initial step of vesicle endocytosis. So collectively, our findings suggest that termination of growth signaling by PTEN is intimately linked and likely co-evolved with the process of endocytosis. We propose that inactivation of growth signals is far more efficient and processive, when signals are presented on discrete incoming vesicle surfaces to which PTEN binds.

See the Reviews

Nature's News & Views - Science Signaling's Editor's Choice

CSHL Press Release

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lolipops Bio-Informatics Student Position Available

Development of a local instance of the cBioPortal for RapidCaP

We are looking for a Software Engineer to design, develop and expand a local instance of the cBioPortal for Cancer Genomics. The cBioPortal, which is developed at Memorial Sloan Kettering Cancer Center, is a web-based resource for human cancer genomics that supports thousands of researchers and clinicians around the globe. We use genome sequencing to understand evolution and therapy resistance of metastasis in the RapidCaP mouse model and our goal is to build a cBio- based instance for visualization, exploration and comparative analysis of the mouse data with human.

Full description

Email: trotman@cshl.edu

   
Postdoc and Student Positions Available

Single Cell Genome Evolution in Metastasis and Therapy

The RapidCaP system affords us a first look at prostate metastasis evolution in a native and fully explorable context. We are looking for enthusiastic scientists that want to understand the nature of the changes that result in the emergence of lethal and therapy-resistant genomes.

Full description

Email: trotman@cshl.edu

   
Trotman Lab wins Pershing Square Sohn Prize

Single Cell Genome Evolution of Metastasis - 5 / 2014

The Pershing Square Sohn Prize for Young Investigators in Cancer Research has identified 5 New York-based scientists and allows them topursue their boldest research at a time when traditional funding is lacking. We are extremely proud and excited to be part of this amazing group of scientists with our project on defining the evolution of prostate metastasis at single cell resolution.

Watch the video interview

The PSS Cancer Resaerch Alliance is committed to connecting its funded scientists with industry to accelerate translation of the bold projects into actionable progress for cancer treatments.

Watch the prize announcement video

   
ribbons Lloyd Named American Cancer Society Fellow

ACS funds research on PTEN activation - 4 / 2014

PTEN is thought to counteract PI 3-Kinase signaling at the plasma membrane where growth hormones activate receptor tyrosine kinases. The generous support by the ACS allows us totake a closer look at where PTEN acts and why.

This research is critical for understanding how we can support the many patients in which PTEN function needs to be boosted to halt the progression of cancer.

   
Publication: RapidCaP, a GEM Against Metastasis

Myc drives PTEN mutant prostate metastasis
Hyejin Cho, 3/ 2014

Genetically Engineered Mouse (GEM) models for Pten-deficient Cancers of the Prostate (CaP) have greatly helped us understand the biology of tumor initiation, but their characteristic of developing lethal primary disease is obstructing research and therapy of the advanced metastatic disease stages. Thus, the genetic requirements needed to trigger metastatic prostate cancer have remained ill defined.

Here we developed RapidCaP, a GEM modeling system that uses surgery for gene manipulation, instead of breeding. It recreates and visualizes human metastatic disease, identifies Myc as a driver of PTEN mutant metastasis, and shows that the recently developed Myc inhibitor, JQ1, can successfully revert metastasis.

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Publication: Does Increased Transcription Precede Gene Amplification in Cancer?

AR regulated gene locus gets co-amplified with AR in metastasis In collaboration with Dawid Nowak, 12/ 2013

In lethal, castration-resistant metastatic prostate cancer (CRMPC), most tumors still rely on the androgen receptor signaling to thrive through various mechanisms such as AR gene amplification. Here, we collaborate with the team of Dr. Michel Tremblay (McGill University, Montréal) to show that a genomic region, previously identified as an hereditary prostate cancer genetic-susceptibility locus, is frequently co-amplified with the AR in CRMPC. Importantly, the common amplified region (CAR), which encodes genes that might contribute to global transcription rewiring, is also AR-regulated. Combined, these results suggest an example of synergistic copy number gain that potentiates AR activity and promotes CRMPC progression.

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Publication: Nuclear PTEN Helps Recovery from Stroke

Ndfip1, a new PTEN regulator in neurons
In collaboration with Adam Naguib, 1/ 2012

 

Loss of blood supply to the brain results in infarcts. To prevent irreversible cell death neurons sharply increase the levels of Ndfip1 protein. This promotes Pten nuclear transport, in concert with the Nedd4 ubiquitin ligase. As a consequence, a transient increase in cytoplasmic Akt can support neuronal survival until blood supply is restored. These findings uncover the first physiological relevance of Pten trafficking in cells.

See a review

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Predicting Prostate Cancer Outcome

PTEN and PHLPP1 status in prostatectomy - 10/ 2011

Measuring combined RNA expression levels of the two tumor suppressor genes PHLPP1 and PTEN could allow for prediction of disease outcome in surgical samples.

See a review

 

   

Publication: A New Tumor Suppressor in Prostate

PHLPP1 blocks prostate cancer
Muhan Chen, 8/ 2011

Our search for the mechanisms behind prostate cancer and its progression to lethal disease has led to identification of the PHLPP genes as critical tumor suppressors. PHLPP1 is frequently degraded at the protein level and its RNA expression is often suppressed in cancers. The DNA copy number alteration patterns allow us to establish a principle for disease progression.

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