Published
Cancer Neuroscience - Future Directions - 4/ 2024
See this link for an updated outlook in Cancer Discovery on emerging questions and techniques for understanding how tumors interact with nerves.
Publication
Lipid Carriers as Anti-Cancer Drug Targets - 12/ 2023
Check out Manojit’s paper on targeting the lipid carrier FABP5 in prostate cancer. This work is the result of a multi-disciplinary team effort that combines chemists and pharmacologists.
Accepted
Carlos at Boston’s MIT for summer research - 2/ 2023
Carlos has been accepted to MIT’s summer science & engineering program. As part of this 5 week program for high school students he will do a mentored research project. Congrats!!
Interview
Cancer’s Got a Lot of Nerve - 8/ 2022
Jeremy Borniger, Northwell Health’s Manish Vira and Lloyd talk with Nautilus’ Lina Zeldovich about their collaboration on the interplay between nerves and cancer.
Mary receives Early Investigator Award from DOD, 8/2022
Congrats on receiving this grant for researching the interface between prostate cancer metastasis and the nervous system.
Career News:
Grinu starts her own lab, 5/2021
Grinu Mathew has started her position as Assistant Professor at the Eppley Institute for Cancer Research at the University of Nebraska Medical Center.
We wish you all the best explaining anterior prostates to clinicians
;-))))
Interview
American Cancer Society Podcast with Lloyd 8/2019
A very special 30 minutes of reflecting on prostate cancer research, its history, future and the most exciting things happening in our lab now.
Great work by team TheoryLab of the ACS - congrats!
Publication: A new way to target MYC
The PHLPP2 Phosphatase supports MYC and metastatic prostate cancer
Project leader: Dawid Nowak, 5/ 2019
5-year survival for prostate-confined tumors is almost 99%. In contrast, the 5-year survival of metastatic prostate cancer is only about 30%. We used our RapidCaP model to find genes that favor metastasis and found that the putative tumor suppressor PHLPP2 actually promotes metastatic disease. PHLPP2 stabilizes the MYC oncogene, a powerful metastasis driver of many cancer types. Our study revealed that without PHLPP2, prostate tumors will remain indolent and not turn lethal by colonizing distant sites in the body. Furthermore, we show that an inhibitor of the PHLPP2 enzyme suppresses MYC..
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.
Publication: Mitochondrial Inhibitors Against Prostate Cancer
Complex I inhibitors can selectively kill PTEN-null Cells
Project leaders: 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.
Career 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!
Publication: The Achilles' Heel of PTEN
Nuclear Import receptor of PTEN protects from cancer -
Project leaders: 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.
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.
Publication: Eavesdropping on Metastasis
Immune signaling accelerates prostate metastasis -
Project leader: 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.
Publication: PTEN Functions on Endocytic Vesicles
Cancer signals are packaged, then presented to PTEN
Project leader: 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
Lloyd 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.
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.
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
Project leader: 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.
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.
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.
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 PTENcould allow for prediction of disease outcome in surgical samples.
Publication: A New Tumor Suppressor in Prostate
PHLPP1 blocks prostate cancer
Project leader: 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.