In a preclinical study (published in Cancer Research), biologist Dr Li Zhang and her team at the  University of Texas at Dallas. showed that the expansion of lung tumors in mice slowed when access to heme (the oxygen-binding molecule in hemoglobin) was restricted. The researchers also showed that those same cancers grew faster when more heme was available than normal.

With an eye toward exploiting cancer’s heme dependency, two of Dr Zhang’s graduate students in the Department of Biological Sciences then engineered and extensively characterised new molecules aimed at starving the cancer cells of the molecule that allows them to proliferate so quickly.

The findings suggest a potential new path forward in treating non-small cell lung cancer (NSCLC), which comprises about six out of every seven cases of lung cancer.

However, the team emphasised that its potential treatment approach is designed to work in tandem with chemotherapy or other forms of cancer remedy, not by itself.

“This method wouldn’t kill tumors; it would delay their growth,” explained Dr Zhang. “So it would not be a stand-alone treatment, but it could replace less effective forms of therapy that rely on inhibition of angiogenesis – the creation of new blood vessels.”

These new results emphasise that tumors create energy using molecules other than glucose – a type of sugar known to feed tumors. Where more heme is being made, more oxygen is consumed to make more adenosine triphosphate (ATP) – the energy-carrying molecule that fuels many activities in living cells. Take the heme away, and cancer cell growth slows down.

Sagar Sohoni and Poorva Ghosh, co-first authors of the study, collaborated to investigate how a series of engineered molecules deny heme to cancer cells. These heme-sequestering peptides, or HSPs, are able to ‘hijack’ heme from the spaces between cells, where tumors would be able to access it, while leaving alone the heme in healthy cells.

“Heme sequestering doesn’t adversely affect the normal cells,” Dr Zhang continued. “They synthesise the little heme they need on their own. Also, our peptide won’t go into cells so it shouldn’t provoke many side effects.”

Demonstrating the reduced progress of heme-starved cancer cells makes a compelling case on its own. Dr Zhang’s team also modified NSCLC cells to allow them to obtain heme faster and those cells behaved as expected – aggressive and invasive, consuming oxygen quickly and putting out more ATP.

“Cancer cells’ energy demands are very high compared to the normal cells around them,” Dr Zhang said. “When more heme is available, NSCLC cells grow and reproduce at an alarming rate.”

The next step is to continue refining the design of the HSPs to create a version for use in humans.


Despite significant advances, only a minority of individuals benefit from immunotherapy to treat cancer, and the reasons why remain unclear.

Immunotherapy research has largely centred on T cells, a type of immune cell that learns to recognise specific proteins and launch an attack. Tumours, however, are a complex mixture of many different cell types, including other immune cells known collectively as tumour-infiltrating myeloid cells. These cells represent alternative targets for immunotherapy, but their role in tumours is still poorly understood.

To shed light on this under-examined family of immune cells, Harvard Medical School researchers based at the Blavatnik Institute, Massachusetts General Hospital, Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital used single-cell sequencing to map the landscape of myeloid cells in tumours from patients with lung cancer.

Their study, published in the journal Immunity, reveals 25 myeloid cell subpopulations, many previously undescribed, with distinct gene expression signatures that are consistent across patients. Most of these subpopulations were also identified in a mouse model of lung cancer, indicating a high degree of similarity in myeloid cells across species.

The findings serve as a foundation for future research to explain the precise roles of myeloid cells in cancer and to assess their potential as targets for new or improved immunotherapies, the authors said.

“Immunotherapy is clearly a transformational approach to cancer treatment, but there are many patients who don’t respond, and the question is why,” said co-corresponding author Allon Klein, assistant professor of systems biology at HMS.

“Part of the answer could certainly lie at the level of myeloid cells, which interact heavily with both tumour cells and T cells,” Klein continued. “By identifying the rich complexity of myeloid cell states in tumours, we now have a powerful starting point to better understand their functions and clinical applications.”

Of particular importance, the authors said, was the finding that myeloid subpopulations can be reliably identified in different human patients and in mice – an observation that underscores the fundamental use of mouse models in immunotherapy research.

“Tumour cells were different in each patient analysed, but the identity of tumour-infiltrating myeloid cells greatly overlapped between the same patients. Also, many myeloid populations were incredibly well conserved across patients and mice,” said co-corresponding author Mikael Pittet, HMS associate professor of radiology at Mass General.

“This is exciting because a growing body of evidence based on mouse studies suggests that myeloid cells can control cancer progression and affect virtually all types of cancer therapy, including immunotherapy” Pittet added.

Myeloid cells – comprised of immune cells including monocytes, macrophages, dendritic cells and granulocytes – are part of the innate immune system, the body’s first and broad line of defence against foreign pathogens. They play an important role in activating the adaptive immune system, including T cells, which can precisely target and destroy pathogens.

Their analyses revealed myeloid cell gene expression signatures that fell into 25 distinct clusters, greatly expanding the number of known myeloid cell states.

They found that dendritic cells, for example – which Pittet and colleagues previously found are critical to successful anti-PD-1 immunotherapy in mice – contained four different subtypes that are largely mirrored between humans and mice. Monocyte subtypes also matched well between humans and mice, while macrophages were both conserved and varied by species.

Neutrophils, which are the most abundant white blood cells in mammals, formed a spectrum of five similar subtypes in humans and mice, with one subset unique to mice. Pittet, in a previous collaboration with Klein, found that neutrophils expressing high levels of the gene Siglecf have tumour-promoting properties. The new analyses corroborated this finding, showing that these neutrophils are highly enriched in tumours.

“Myeloid cell populations are complex, but we see the same complexity across patients and species, which gives us confidence that insights in mouse models can be translated to humans,” said Pittet.

With the landscape of myeloid cell gene-expression patterns mapped, scientists can mine existing datasets of patients with known clinical outcomes to look for the presence of a given population of myeloid cells and assess their relationship with patient survival.

The team also looked at whether the behaviour of myeloid cells in tumours could be gleaned by sampling myeloid cells circulating in blood and found a poor relationship between the two.

In addition to immediate basic and translational research opportunities, the study findings inform the work of initiatives such as the Human Tumor Atlas, an effort to map the landscape of all cell types in the human body, and the Human Tumor Atlas Network, an effort to create atlases of a wide variety of cancer types in cellular and molecular detail.


Relapse of disease following conventional treatments remains one of the central problems in cancer management, yet few therapeutic agents targeting drug resistance and tolerance exist.

New research conducted at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) found that a microRNA – a small fragment of non-coding genetic material that regulates gene expression – mediates drug tolerance in lung cancers with a specific mutation.

The findings, published in Nature Metabolism, suggest that the microRNA could serve as a potential target for reversing and preventing drug tolerance in a subset of non-small-cell lung cancers.

“These results were a surprise and represent a total novel finding in the area,” said senior author Frank J. Slack, PhD, Director of the HMS Initiative for RNA Medicine at the Cancer Center at BIDMC.

“We have identified a novel pathway required for drug tolerance that is regulated by a microRNA. Targeting this microRNA reduces tolerance, suggesting a potential new approach for treatment of lung cancer.”

Lung cancer is the leading causes of cancer-related deaths among both men and women. As a class, non-small cell lung cancers – which comprise about 85 percent of lung cancer diagnoses – tend to be less aggressive but harder to treat than small cell lung cancers. About one in 10 non-small-cell lung carcinomas carries a mutation to a protein called EGFR on the surface of the cancer’s cells.

Since 2003, several medications that block the activity of the EGFR protein – a class of drugs called tyrosine kinase inhibitors – have received FDA-approval for the treatment of EGFR-positive lung cancers. Despite patients’ sometimes dramatic initial response to these medications, however, many patients eventually relapse as their cancer develops resistance to the treatment. By studying drug resistant tumour cells, Slack and colleagues identified the key players driving the development of drug resistance.

“In this study, we discovered that a microRNA known as miR-147b is a critical mediator of resistance among a subpopulation of tumour cells that adopt a tolerance strategy to defend against EGFR-based anticancer treatments,” said Slack, who is also the Shields Warren Mallinckrodt Professor of Medical Research, Departments of Pathology and Medicine, Harvard Medical School. “We are currently testing the idea of targeting this new pathway as a therapy in clinically relevant mouse models of EGFR-mutant lung cancer.”


A mechanism for activating the immune system against cancer cells allows immune cells to detect and destroy cancer cells better than before.

The study was led by Professor Nick Haining, at Harvard Medical School, and was co-authored by Professor Erez Levanon, doctoral student Ilana Buchumansky, of the Mina and Everard Goodman Faculty of Life Sciences at Bar-Ilan University, and an international team.

The focus of the study was to develop a mechanism that routinely serves the cell by marking human virus-like genes in order to avoid identifying them as viruses. 

Prof Levanon, together with the Harvard team, discovered during the study that when inhibiting this mechanism, the immune system can be harnessed to fight cancer cells in a particularly efficient manner, and also more effectively in both lung cancer and melanoma.

“We found that if the mechanism is blocked, the immune system is much more sensitive. When the mechanism is deactivated, the immune system becomes much more aggressive against the tumor cells,” said Prof Levanon.

In recent years, a new generation of cancer drugs has been developed which blocks proteins that inhibit immune activity against malignant tumors. These drugs have shown remarkably poisitve success in several tumor types, in some.

This year’s Nobel Prize in Medicine was awarded to James Allison and Tasuku Honjo, who discovered the key genes of this mechanism.

Despite this achievement, the current generation of drugs helps only a small number of patients, while most of the drugs fail to cause the immune system to attack the tumor.

The research team hope that the new discovery will allow enhanced activity of the immune system to attack cancer cells. A number of companies have already begun research to screen for drugs that will operate on the basis of this discovery.

The study was published in the journal Nature.