Two studies by HSCI scientists advance our understanding of cancer

Two new studies by Harvard Stem Cell Institute (HSCI) scientists give important insights into lung and liver cancers, and have potential implications for cancer treatment.

Carla Kim, Ph.D., HSCI Executive Committee member, has identified a caveat for a proposed lung cancer therapy: while the therapy fights against general tumor cells, it also boosts cancer stem cells that lead to tumor development. Published in Nature Communications, Kim’s study identifies an alternate therapeutic approach that takes cancer stem cells into account.

Fernando Camargo, Ph.D., HSCI Principal Faculty member, has identified a protein involved in liver cancer that could be targeted by a therapeutic drug. The protein is the first ‘druggable’ target identified in the well-studied Hippo biological pathway. Camargo’s study is published in Nature Communications.

Kim and Camargo are both part of the Stem Cell Research program at Boston Children’s Hospital.

Caveat for lung cancer treatment

 

Proteins that control which genes are turned on or off in a cell can be targeted by ‘epigenetic’ therapies. One particular epigenetic therapy inhibits G9a, a protein that promotes cancers including lung adenocarcinoma. Kim’s new study, led by lab member Samuel Rowbotham, Ph.D., calls this strategy into question.

“People had looked at cell lines from lung tumors and found that they are sensitive to drugs inhibiting G9a,” said Rowbotham. “In general tumor cell populations, these drugs would slow down growth or even kill the cells. But we found that these drugs were also making the surviving tumor cells more ‘stem-like’. We predicted that this would advance disease progression, and that is what we saw.”

There are two reasons why this downside to G9a therapy might not have been noticed before. Previous studies only looked at cell lines, not animal models, and cancer stem cells are hard to detect.

“Earlier studies couldn’t see that cancer stem cells were still around, and there’s more of them when you treat with these drugs,” said Kim. “Because they’re such a small fraction of the tumor, anything that affects them can be missed.”

After realizing that G9a might not be an ideal therapeutic target, the researchers identified an alternative approach: targeting a group of proteins that have the opposite chemical activity as G9a.

When Rowbotham lowered the expression of these proteins, adenocarcinoma cells looked less like cancer stem cells in a dish, and behaved less like cancer stem cells in mice. When he treated mice with a compound that inhibits these proteins, tumor size decreased.

The team is now doing further studies to explore this type of inhibitor as a potential treatment for lung cancer.

A ‘druggable’ target in liver cancer

 

Cancer develops when cell growth goes unchecked, and a biological pathway called Hippo — which regulates the size of organs — is involved. The protein YAP is a major player in the Hippo pathway and contributes to many types of tumors.

Although previous studies have shown that YAP is involved in tumor development, the structure of the protein prevented any therapeutic drugs from binding to it. The new study from the Camargo laboratory has found that another protein, NUAK2, is part of the same pathway, and can be targeted by a therapeutic compound.

“The Hippo pathway, and especially YAP, has been hard to target with drugs,” said Camargo. “This is the first demonstration of a ‘druggable’ molecule that could be targeted in any type of tumor driven by YAP.”

Wei-Chien Yuan, Ph.D., who led the study, used human liver cancer cell lines and a mouse model of liver cancer to search for genes that are influenced by YAP. She found that NUAK2 is critical for YAP-driven cancer growth, and that a small-molecule compound that inactivated NUAK2 was able to curb cancer cell proliferation.

“We want to see if we can make the compound more selective,” said Yuan. “It has other nonspecific targets, so we need to modify it to make it usable.”

In future studies, the researchers will also test the strategy of inhibiting NUAK2 in other YAP-driven cancers, including oral cancers, head and neck squamous carcinomas, pancreatic cancers, ovarian cancers, and squamous cell skin cancers.

Read more

Boston Children’s Hospital Vector blog posts

• Proposed cancer treatment may boost lung cancer stem cells, study warns
• ‘Druggable’ cancer target found in pathway regulating organ size

Scientific papers

• Rowbotham, S. P. et al. (2018). H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression. Nature Communications. DOI: 10.1038/s41467-018-07077-1
• Yuan, W.-C. et al. (2018). NUAK2 is a critical YAP target in liver cancer. Nature Communications. DOI: 10.1038/s41467-018-07394-5

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